Liver function test valuesSignificance, interpretation, algorithms and peculiarities

Ali Canbay, Magdeburg University Hospital (Germany) Jan Best, Guido Gerken, Essen University Hospital (Germany)

GPT

NAFLD

GOT

GGTAST

ALTGLDH

LDH

AP

HepatitisASH

NASH

ALDHCC

CCC

Albumin

INRCholinesteraseNH3AIH

HEAMA

SMASLA

pANCA

anti-HCV

HAV IgM

HBc IgM

HEV IgM

HBV DNA

HCV RNA

TA HBsAg

ANA

Bilirubin

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Ali Canbay, Magdeburg University Hospital (Germany) Jan Best, Guido Gerken, Essen University Hospital (Germany)

Liver function test valuesSignificance, interpretation, algorithms and peculiarities

Address for correspondence: Prof. Dr. Ali CanbayDepartment of Gastroenterology, Hepatology and Infectious DiseasesMagdeburg University HospitalOtto-von-Guericke-University Magdeburg Leipziger Str. 4439120 MagdeburgGermanyTelephone: +49 391 67-13100Fax: +49 391 67-13105E-Mail: kghi@med.ovgu.de

Co-authors: Dr. Jan Best Prof. Dr. Guido Gerken Department of Gastroenterology and Hepatology Essen University Hospital University of Duisburg-Essen Hufelandstr. 55 45122 Essen Germany

Conflict of interest: The authors declare that there are no conflicts of interest.

Summary 4

Introduction 5

1. Clinical procedure 6

2. Differential diagnosis of parenchymal liver diseases 11

3. Differential diagnosis of cholestatic liver diseases 16

4. Parameters of hepatic synthetic function 20

5. Diagnostics for significantly elevated LFT values 21

6. Diagnostics for chronically elevated LFT values 25

6.1. Viral hepatitides 256.2. Non-alcoholic fatty liver disease 266.3. Alcoholic liver disease 286.4. Autoimmune liver diseases 28 6.5. Metabolic liver diseases 30 6.6. Lysosomal storage diseases 30 6.6.1. Gaucher‘s disease 30 6.6.2. Lysosomal acid lipase deficiency 316.7. Less common causes 31

7. Conclusions for clinical practice 33

Abbreviations 34

References 35

Contents

3

Summary

Liver diseases, both acute and chronic, are problems which are frequently en-countered in clinical routine and which place sometimes considerable burdens on the public health system. Along with acute liver diseases (toxic liver failure, acute viral hepatitides etc.), chronic liver diseases in particular, such as viral hep-atitides and, with mounting frequency, also fatty liver diseases (alcohol-related/ALD and non-alcohol-related/NAFLD), lead, via hepatic fibrosis, to liver cirrhosis and hepatocellular carcinoma (HCC) as the final stage. As a result, it is becoming increasingly important to detect liver diseases at an early stage, with the aim of providing timely therapy and correcting predisposing factors.

As the central metabolic organ, the liver is very active with an extremely broad spectrum of functions and produced factors, and therefore also interacts directly with other organs such as the heart and kidneys.

Elevated liver function test (LFT) values are frequently found in clinical practice and represent a challenge for the treating physician. While timely detection of hepatopathy requiring treatment has prognostic implications, there is also the need to avoid overdiagnosis. Liver diseases that remain undiagnosed or are di-agnosed too late as well as irrational diagnosis place considerable burdens on both patients and the public health system. It is therefore important to detect liver diseases at an early stage in order to use the currently available treatments to avoid long-term sequelae, such as liver cirrhosis and its complications or the emergence of HCC. This brochure aims to present a diagnostic algorithm de-signed to enable efficient diagnosis. It describes important liver diseases and the laboratory constellations typical of them and presents additional necessary serological and instrument-based test methods.

The contents of this brochure are based on the latest literature as well as on ex-perience drawn from day-to-day clinical practice. Because the knowledge gained through research and clinical practice is always subject to new developments, we make no claims to completeness.

4

Introduction

It is estimated that more than 5 million people in Germany suffer from a liver disease. In the 35–59 age group, alcoholic liver disease is the second and third most frequent cause of death in men and women, respectively [1]. In many of these patients, advanced liver disease is only diagnosed at a late stage, even though elevated liver function test (LFT) values were already apparent years ear-lier. Elevated ALT (alanine aminotransferase) can be observed in approx. 25% of Germans [2]; in the absence of symptoms, these values are frequently interpreted as harmless or are wrongly seen as being linked to the use of drugs or to some other systemic disease.

This may be problematic for individual patients because even commonly di-agnosed non-alcoholic fatty liver disease (NAFLD) may lead to cirrhosis and its complications, e.g. portal hypertension, liver failure and HCC, in a considerable proportion of patients. Every initial diagnosis of elevated LFT levels should, as a matter of course, be subject to further investigation. In addition to the medical history and the physical examination, laboratory markers for parenchymal liver damage, cholestasis and hepatic synthesis constitute the cornerstones of the initial diagnosis of liver disease.

Laboratory diagnostics aid in the classification of the damage pattern (i.e. hepat-ic, cholestatic, toxic or mixed) for a differential diagnosis as well as in assessing the degree of severity and the prognosis of the disease. Further diagnostics using immunological and molecular markers, imaging techniques and biopsy can be initiated consecutively.

5

1. Clinical procedure

If liver disease is suspected, initial diagnostics should include a blood count and the determination of transaminases, GGT (gamma-glutamyl transferase) and al-bumin levels (Fig. 1). In 95% of all patients with liver diseases at least one of the following values is elevated: AST (aspartate aminotransferase, ALT (alanine ami-notransferase) or GGT [3]. Further diagnostics are essential if elevated LFT values persist (generally for longer than 6 months), are associated with clinical symp-toms or are higher than twice the norm. The medical history interview should cover the patient‘s personal history, work history (e.g. exposure to chemicals etc.), risk factors (e.g. promiscuity) as well as travel and drug history (incl. use of medicinal plants) over the previous 6 months, in addition to any prior medical interventions. Along with abdominal status and the possibility of jaundice, the physical examination should focus on extrahepatic manifestations of chronic liver disease such as spider naevi, palmar erythema, smooth red tongue, lacquered lips, temporal wasting (especially resulting from alcohol intoxication) etc. as well as signs of portal hypertension (splenomegaly, caput medusae etc.). These basic diagnostics can make it possible to draw initial conclusions about the etiology and to differentiate between acute and chronic damage as well as to assess the degree of severity of the liver disease.

The laboratory parameters obtained from basic diagnostics enable the differenti-ation of the specific pattern of liver damage and so provide valuable indications as to the cause of the liver disease. „Liver enzymes never lie!“ AST, ALT and GLDH (glutamate dehydrogenase) are indicators of parenchymal (hepatic) dam-age. Impaired biliary excretion, represented by the so-called ‚cholestatic’ pattern, is characterized by elevated AP (alkaline phosphatase), GGT and bilirubin. Domi-nant GGT elevation suggests a toxic damage pattern (Fig. 1). Not every instance of liver damage conforms strictly to this pattern; there are also mixed types. The parameters of hepatic synthesis are the INR (international normalized ratio) as well as albumin and cholinesterase levels. When taking an overview of the bio-markers for interpretation purposes, it is vital to consider the various half-lives in order to avoid any misinterpretations which could otherwise result. It should also be kept in mind that normal transaminase levels do not rule out liver disease or infectious viral hepatitides (Tabs. 1–3). The valid normal values should be evalu-ated critically in the light of current data, because the original control collectives were probably set too high [4, 5], as historically the prevalence of cases of non-vi-rus-associated hepatopathy (NAFLD) and chronic hepatitis C disease were either unknown or underestimated.

6

7

Fig. 1: General increase in LFT values

Isolated bilirubin Cholestatic

T-bilirubin, AP, GGT ALT/AST

Non- mechanical

Non- mechanicalMechanical

Liver dialysis?

MRCP/ ERCP

CT angiography MRI angiography

Hepatic

Infections Sepsis, TPN

Drugs Post-op

Hemolysis Hematoma

Gilbert’s syndrome

Stone, sludge Cholangitis Cholecystitis Pancreatitis

Ischemic Viral

- Hepatitis A, B, C (D, E)

- CMV, EBV, HSV

Drugs Bacterial

General increase in LFT values

Duplex sonography/elastography (FibroScan®)

8

Tab. 1

Biochemical markers of parenchymal liver injury

Alanine aminotransferase ALT

Synonym: glutamate-pyruvate transaminase GPT

· Half-life 47 hours· Normal range (♂ < 50 U/L; ♀ < 35 U/L)· Liver-specific if markedly elevated values

· Localization only in cytoplasm · Elevated values in acute hepatitis, slightly elevated in liver tumors or drug-induced toxic damage

Aspartate aminotransferase AST

Synonym: glutamate-oxaloacetatetransaminase GOT

· Half-life 17 hours· Normal range (♂ < 50 U/L; ♀ < 35 U/L)· Very sensitive· Non-specific, also elevated in myo- cardial infarction, skeletomuscular diseases, hemolysis

· Localization in cytoplasm and in mito-chondria

· Significantly elevated values in acute viral, alcoholic and toxic hepatitis

Glutamate dehydrogenase GLDH

· Half-life < 18 hours· Normal range (♂< 7 U/L; ♀ < 5 U/L)· Liver-specific if markedly elevated values

· Exclusively mitochondrial localization· Elevated values if centroacinar dam-age: hypoxia, acute (toxic) hepatitis, obstructive jaundice

9

Tab. 2

Biochemical markers of impaired biliary secretion or cholestasis

Alkaline phosphatase AP

· Half-life 1–7 days· Normal range (♂ 25–124 U/L; ♀ 25–100 U/L)

· Predominantly membrane-bound· Not liver-specific (isoenzymes in liver, bones, kidneys, intestine, placenta)

· Elevated in cholestasis, hepatic infil-tration, slight increase in hepatitis and with drugs

Bilirubin excretion in urine · Elevated in hepatic and post-hepatic jaundice

Gamma-glutamyl transferase GGT

· Half-life 3–7 days· Normal range (♂ < 55 U/L; ♀ < 35 U/L)· Membrane-bound· Liver-specific· Elevated in biliary cholestasis, toxic damage

Serum bilirubin indirect/direct

Total bilirubin: 0.2–1.1 mg/dL· Metabolites of heme· Direct

- Normal range 0–0.2 mg/dL (conjugated)

- Elevated in hepatic/post-hepatic jaundice

· Indirect - Normal range 0.3–1.2 mg/dL - Elevated in pre-hepatic jaundice

10

Tab. 3

Parameters of hepatic synthesis and detoxification

Albumin · Normal range 3.4–4.8 g/dL· Transport protein· Anti-oxidative/anti-inflammatory

Ammonia · Normal range 13–55 μmol/L· Parameter of detoxification function· Slight correlation between ammonia level and severity of encephalopathy

Cholinesterase · Normal range 4.9–11.9 kU/L· Prognosis factor in fulminant liver failure, liver cirrhosis and after liver transplant

· False elevated after fresh plasma infusion

Prothrombin time(PT, Quick value)International normalized ratio (INR)

· Normal range PT: 70–130%· Normal range INR < 2· Poor prognosis when values are markedly low

· Vitamin K dependency

11

2. Differential diagnosis of parenchymal liver diseases

ALT is a liver-specific enzyme which, due to its cytoplasmic localization in the hepatocytes, can be detected serologically if even minor parenchymal liver dam-age is present. Because of its sensitivity, this parameter is also very suitable for preventive screenings as part of primary care.

AST is a highly sensitive indicator of a hepatocellular damage pattern, but pro-vides only a low degree of specificity. However, due to its stronger mitochondrial localization, it can be used to predict the severity of cell necrosis. The De Ritis ratio, as the ratio between AST and ALT, facilitates differentiation between fairly minor liver injury (De Ritis < 1) and severe liver injury (De Ritis > 1) as is present in chronic hepatitis or liver cirrhosis.

GLDH is also located in the mitochondria and indicates a centroacinar pattern of liver damage, which occurs with severe parenchymal damage and in cases of acute intoxication (e.g. in death cap [mushroom] poisoning) and hepatic per-fusion disorders. In cholestatic liver diseases, GLDH is only moderately elevated (Fig. 2).

Fig. 2: Enzyme localization in hepatocytes/cholangiocytes (For key to abbreviations, see Tabs. 1–3)

Cholestasis parameters

Bilirubin

AP

GGT

GLDH

Transaminases

Synthesis parameters

N

Bile acids

Albumin Cholinesterases

PT (factors I, II, V, VII, X)

AST

ALT

Transaminase levels make it possible to draw inferences about the etiology of the liver disease. For example, a marked rise in the transaminase levels (> 10–50 times the norm) suggests the presence of fulminant forms of viral or drug-induced toxic hepatitis, but also ischemic damage or malignant hyperthermia. Moderate trans-aminase rises (> 5 times the norm) can occur in mild viral hepatitides as well as in drug-induced toxic (Fig. 3), alcohol-toxic or recreational drug-induced (cocaine, ecstasy) hepatitides. Slightly elevated transaminase levels point to non-alcoholic fatty liver diseases or liver tumors but also occur in cholestatic liver diseases and in pre-existing liver cirrhosis (“burnt-out” cirrhosis), in which the transaminase levels may be within normal values. If there is evidence of elevated transaminase levels, further differentiation into acute or chronic liver disease is needed. This differenti-ation is made on the basis of a medical history and clinical examination. Both the evidence of thrombocytopenia as well as typical sonographic findings can indicate chronic liver disease.

In acute liver disease with moderately elevated LFT values and no signs of liver insufficiency, transaminase levels should be rechecked within 3 months. If trans-aminase levels remain persistently elevated or show a rising tendency, further di-agnostics are necessary. Viral hepatitis A, B/D, C or E should always be ruled out (Fig. 4). If viral serology is negative, the subject should be screened for metabolic diseases involving the liver (hemochromatosis, Wilson‘s disease, diabetes mellitus, celiac disease, Gaucher‘s disease, LAL-D etc.). In addition, autoantibody (ANA, AMA, SMA, SLA, pANCA) and immunoglobulin levels should be determined and serum electrophoresis should be carried out as an indication of autoimmune hep-atitis (AIH). If the results are still negative, the next step should be to investigate for less common causes such as infection with hepatotropic viruses, bacteria, fungi

12

Fig. 3: Elevated drug-induced LFT values

ALT AP ALT/ AP ratio

Hepatocellular ≥ 2 x Elevation Normal High (≥ 5)

Cholestatic Normal ≥ 2 x Elevation Low (≤ 2)

Mixed type 2 x Elevation 2 x Elevation

Mild GLDH elevation (> 7–200 U/L) with all types of damage

13

Fig. 4: Hepatitis diagnostics

Virus?

In parenchymal damage: ALT dominant!!

Acute hepatitis:

AST > 1000–3000 U/LALT > 2000–5000 U/L

GLDH > 10–100 U/L GGT > 100–300 U/LAP > 100–300 U/LT-bilirubin > 5–15 mg/dL

HBsAg (+)

HBc IgM (+)HBV DNA (+)

HBc IgG (+)HBV DNA (+)

HBcAg (+)

Chron. HBV

Acute HBV

HCV RNA (+)

anti-HCV (+)

HCV

HAV IgM (+)

Acute HAV Acute HEV

HEV IgM (+)(HEV RNA)

or parasites. In addition, even if the medical history gives no cause for concern, it should be kept in mind that the patient may have withheld information on drug or alcohol consumption. A useful approach here would be to screen the urine for drugs, determine the CDT (carbohydrate-deficient transferrin) or ethyl glucuronide levels in the urine or take a hair sample (Fig. 5). Elevated transaminase may also

occur in connection with other systemic diseases, a fact that should be taken into account in the differential diagnosis (Tab. 4). False-positive elevated transaminase readings may occur with hemolysis, intense physical activity, increased protein in-take or prolonged fasting as well as postprandially.

14

Fig. 5: Differential diagnosis: ASH or NAFLD/NASH

ASH?Metabolic syndrome?

NAFLD?

Transaminases

MCV/IgA/CDT/ ethyl glucuronide

GGT > 100–1000 U/LAP > 100–300 U/LT-bilirubin > n–5 mg/dLAST > 300–500 U/L ALT < 200 U/L

GGT > 100–300 U/LAP > 100–300 U/LT-bilirubin > n–3 mg/dLAST < 50 U/LALT > 50 U/L

ObesityDiabetes

Hyperlipidemia

AST/ALT ratio ≥ 2:1

AST/ALT ratio < 2:1

GLDH> 10–100 U/L

AST dominant ALT dominant

15

Tab. 4

Systemic diseases involving the liver

Intestinal diseases Celiac disease, ulcerative colitis, Crohn’s disease

Cardiomyopathies Myocardial infarction, myositis, tachycardia/arrhythmia, heart surgery

Vascular diseases Pulmonary embolism (with right ventricular strain)

Musculoskeletal disorders

Progressive systemic muscular dystrophy, polymyositis, dermatomyo-sitis, status epilepticus, heavy physical activity

Endocrine diseases Addison‘s disease, hypo-/hyperthyroidism

3. Differential diagnosis of cholestatic liver diseases

The parameters for detecting cholestasis are GGT and AP. Both enzymes are localized in bile duct epithelial cells (see Fig. 2). GGT is an enzyme with high liver specificity which can be elevated in both cholestatic liver diseases and in toxic damage (nutritive, drug-induced or alcohol-toxic) or malignant infiltra-tion (Figs. 6 and 7). AP elevation should always be interpreted only in con-nection with GGT and total bilirubin because this enzyme is liver unspecific and because very high values can also occur with osteolytic metastases, hyperpara-thyroidism, Paget‘s disease of bone and during pregnancy. Bilirubin is likewise elevated in cholestatic diseases (Fig. 8), but also potentially in advanced liver cirrhosis. Thus, this parameter should not be used in isolation as an indicator of cholestasis. Clinically, hyperbilirubinemia with a total bilirubin count of 3 mg/dL and above correlates with manifest dermal jaundice (scleral jaundice correlates with counts starting as low as 2 mg/dL). In order to classify hyperbilirubinemia, it is essential to differentiate between direct and indirect bilirubin elevation as this allows for categorization in terms of pre-, intra- or post-hepatic jaundice (Fig. 9). Indirect bilirubin occurs in connection with the breakdown of hemo-globin and other porphyrin derivatives, is bound to albumin in serum and is transported to the liver. In hepatocytes, conjugation of indirect to direct bilirubin occurs with glucuronic acid, after which the bilirubin is secreted in bile. For ex-ample, pre-hepatic jaundice with dominant elevation of indirect bilirubin occurs mainly as a result of excessive hemolysis or also with large hematomas or inef-fective hematopoiesis. Elevated levels of direct bilirubin can also be present in parenchymal liver diseases such as cholestatic forms of viral hepatitides, drug-in-duced toxic damage and sepsis. Without concomitant transaminase elevation,

16

Fig. 6: LFT values in malignant infiltration

Malignant infiltration

Isolated instances of elevated GGT and LDH are associated especially with lymphoma infiltration!!

AST > 500–1000 U/LALT > 500–1000 U/L

GLDH >10–100 U/LLDH >1000 U/L

GGT >1000–2000 U/LAP > 500 U/L

T-bilirubin > n–5 mg/dL

the rarer enzyme defects of glucuronidation and bilirubin transport are possible. An exception to this is Gilbert’s syndrome, an asymptomatic type of enzyme defect, which is commonly encountered as an incidental serological finding with isolated indirect bilirubin elevation. Gilbert’s syndrome likely constitutes a predis-posing factor for drug-induced toxicity. Elevated levels of direct bilirubin are char-acteristic of post-hepatic jaundice and occur in cases of impaired bile drainage (Fig. 9). This is regularly associated with elevated AP and GGT levels. Abdominal sonography is obligatory as part of initial diagnostics and can frequently be used to confirm a diagnosis of cholecystitis, choledocholithiasis, or pancreatic tumors and cholangiocellular carcinomas.

Some individual pharmaceuticals, such as salicylates, methotrexate, vitamin K, anabolic agents, azathioprine, allopurinol, steroids, tuberculostatic drugs etc., can also lead to hyperbilirubinemia.

17

Fig. 7: Algorithm for elevated GGT levels

GGT

GGT > 500 U/L GGT 100–300 U/L

Unspecific/non-cholestatic

Bile duct obstruction?

AP > 500–1000 U/LGGT > 500–1000 U/L

Isolated GGT > 500–2000 U/L

AP < 500 U/LGGT > 1000 U/L

Toxic?Malignant

infiltration?

Sonography Cross-sectional imaging

Bile ducts dilated

Hepato- megaly

Normal Mass

18

Fig. 8: Algorithm for elevated AP levels

AP

GGT GGT normal

Bacterial cholangitis?

AP > 100–500 U/LElevated bilirubin

LeukocytosisCRP

Procalcitonin

Bile duct obstruction?

AP > 500–1000 U/L Elevated bilirubin

Extrahepatic causes

(Bone metabolism or elevated as isolated parameter in cases of

bone metastases)

Determine bone AP (BAP) separately where

appropriate

19

Fig. 9: Algorithm for elevated bilirubin levels

Bilirubin Biliary obstruction ≤ 15 mg/dLHemolysis ≤ 5 mg/dL

Transaminases (TA)

TA /n, AP

CholestasisCT, US

FeverSepsis

TA normal

Bile ducts normal

Bile ducts dilated

ERCP Biopsy ERCP

TA

HepatitisSyndromes

(Dubin-Johnson, Rotor, Gilbert)

4. Parameters of hepatic synthetic function

Although cholinesterase is the most sensitive parameter of hepatic synthesis, its significance is limited due to its half-life. The value is reduced early on in all chron-ic liver diseases and in liver cirrhosis, but is also reduced in metabolic diseases, such as diabetes mellitus and hyperlipidemia, in malnutrition and hypoalbumin- emia, as well as when taking various drugs (e.g. theophylline, atropine, caffeine, codeine, estrogen, morphine, corticosteroids, vitamin K). Cholinesterase is bound to albumin, and because of its half-life (7–10 days) tends to be an indicator of acute liver insufficiency.

Albumin is a protein formed in the liver that is necessary for the transport of various substances (hormones, drugs) in the blood and at the same time plays an important role in intravascular oncotic pressure. Current data indicate that albumin has antioxidative properties in that it binds oxygen radicals [6]. Com-promised hepatic synthetic function in liver diseases leads to hypoalbuminemia. As a consequence, the intravascular oncotic pressure is reduced and fluid is sub-ject to extravascular diffusion, which is manifested clinically by edema, pleural effusions and the formation of ascites. Also, albumin’s function as a transport protein is impaired, which may lead to changes in drug concentrations and in the electrolyte balance. Albumin is a parameter which is of major prognostic sig-nificance in the classification of liver cirrhosis according to the Child-Pugh score, with bilirubin and INR serving as further parameters of hepatic synthetic func-tion. At present, the INR value plays an important role for liver transplant listing in the context of the MELD (Model for End-stage Liver Disease) score, which was originally developed to aid in prognosis estimates for planned TIPS (transjugular intrahepatic portosystemic shunt) implants. The INR reflects the synthetic capac-ity of vitamin K-dependent coagulation factors. However, current data indicate that when INR values are significantly elevated (e.g. in liver cirrhosis or acute liver failure [ALF]) without substitution of coagulation factors, despite intervention (central venous catheters [CVC], liver puncture) no elevated bleeding tendency occurs [7]. The INR is also elevated when taking coumarin derivatives and with vitamin K deficiency. Other non-vitamin K-dependent factors synthesized in the liver are antithrombin III, fibrinogen and proteins S and C.

The liver’s detoxification function is roughly assessed in the laboratory on the ba-sis of ammonia levels. Ammonia is a product of protein catabolism and is elimi-nated from a healthy liver in the urea cycle. This detoxification capacity decreases in advanced liver diseases or ALF, which causes the ammonia level in the blood to rise and which is clinically manifested in the form of hepatic encephalopathy. The degree of encephalopathy does not correlate, however, with the ammonia

20

level. Determining the level of ammonia in the blood is very prone to error and should be conducted within an hour with a sample that was cooled immediately after extraction.

5. Diagnostics for significantly elevated LFT values

Acute liver failure (ALF) is defined as a sudden (within 28 days) or subacute (up to 6 months) increase in transaminase and bilirubin levels with coagulopathy and the emergence of hepatic encephalopathy to any extent whatsoever (MHE-HE stage IV) in patients with no pre-existing liver disease. In terms of clinical prognosis, it is important to clearly differentiate ALF from both liver failure with pre-existing liver disease without cirrhosis (acute-on-chronic) and liver failure with existing cirrhosis (acute-on-cirrhosis), as both of these are associated with a considerably poorer prognosis [8]. The King’s College criteria or Clichy criteria are tried and tested indicators for a liver transplant and help provide a relatively specific estimate of the prognosis in the event of liver failure, though with signif-icant limitations as regards predicting spontaneous survival [9, 10]. As a result, newer scores, such as the ALFED (ALF Early Dynamic) model or the SOFA (Sep-sis-related Organ Failure Assessment) score, have been developed, which enable better prognostic estimates, though also with limitations, so that ultimately clin-ical appraisal by experienced hepatologists and transplant practitioners remains indispensable. More recent publications confirm that the MELD score also has a high degree of prognostic relevance when estimating ALF survival probability [11]. Other parameters, such as HDL (high-density lipoprotein) cholesterol or thy-roid gland parameters (TSH, T4 and T3) can be taken into account as additional markers for estimating prognosis [12–14].

The most common causes of ALF are collated in Table 5. Quickly identifying the cause has implications for the prognosis of ALF. In order to ensure that a specific therapy can be started promptly, laboratory tests are required in addition to a clinical examination, the patient’s medical history and frequently also third-par-ty medical histories. Initial laboratory examinations must include screening for drugs in the urine or drug concentrations in serum, viral serology, autoantibodies (ANA, AMA, SLA, LKM), a pregnancy test for women of child-bearing age, ceru-loplasmin in serum, copper in the urine, iron, ferritin and transferrin saturation.

21

Immediate abdominal imaging should be performed to exclude a vascular origin (e.g. Budd-Chiari syndrome). When the findings in patients who are cardiopul-monary stable are unclear, many centers have established the value of prompt minilaparoscopy for macroscopic liver assessment and low-complication biopsy with the possibility of coagulation even in patients with coagulopathy [15]. Any AIH not detected with the usual autoantibodies as well as the rarer granulo-matous diseases (e.g. sarcoidosis) can be detected in this manner and treated without delay. Another low-complication alternative for the bioptic identification of an unexplained, acute liver disease is a transjugular liver biopsy, though this includes significantly fewer portal fields and offers no possibility of inspection.

Examples of typical laboratory constellations for acute right-sided cardiac insuffi-ciency, paracetamol intoxication and acute AIH are listed in Figures 10a–c.

22

Tab. 5

Causes of acute liver failure

Viral hepatitides Hepatitis A, B, C, (B+) D, E, HSV, EBV, CMV

Acute intoxication Acetaminophen, Amanita phalloides

Idiosyncratic toxic reaction

Ecstasy, phenprocoumon, tetracycline, halothane, isoniazid, anabolic agents, herbal medicines

Immunological causes AIH, graft-versus-host disease

Metabolic causes Wilson‘s disease, a1-antitrypsin deficiency, non-alcoholic steatohepatitis (NASH), very rare

Causes associated with pregnancy

Acute fatty liver of pregnancy, HELLP syndrome

Vascular origin Budd-Chiari syndrome, ischemia/shock, veno-occlusive disease

23

Fig. 10a: Acute congestion of the liver

Before the event, slightly elevated TA and good coagulation

Decline in liver parameters/ improved coagulation

in approx. 5–7 days

Slow rise in bilirubinSlow rise in GGT/AP values

Slow drop in AST/ALT values

Acute right-sided cardiac insufficiency/ischemic hepatitis

Recompensation/reperfusion

Good prognosis Poor prognosis

12–24 h later

AST > 1000–10000 U/L

ALT > 1000–3000 U/L

LDH > 1000–10000 U/L

GLDH > 1000–3000 U/L

Bili n–2 mg/dL GGT n–100 U/LAP n–150 U/L

INR > 3PT (Quick) < 20%

BNP Trop I

MyoglobinD-Dimer

24

Fig. 10b: LFT values in acetaminophen intoxication

Acetaminophen intoxication

Parenchymal damageAST dominant!!

AST > 1000–20000 U/LALT > 1000–10000 U/L GLDH > 100–500 U/L

GGT > 100–300 U/LAP > 100–300 U/L

T-bilirubin > 2–5 mg/dL

Fig. 10c: LFT values in acute autoimmune hepatitis

Autoimmune hepatitis

Parenchymal damageALT and AST dominant!!

Autoantibodies can be negative!

AST > 1000–3000 U/LALT > 1000–3000 U/L GLDH > 50–100 U/L

GGT > 100–300 U/LAP > 100–300 U/L

T-bilirubin > 10–15 mg/dL

25

6. Diagnostics for chronically elevated LFT values

Chronic liver disease is often asymptomatic until decompensation occurs at an advanced stage of hepatopathy. In the early stage, elevated LFT values lead to the incidental detection of the disease, which should then prompt further diag-nostics. If LFT values remain persistently elevated, it is especially important that the cause be clarified, rather than generally assuming the presence of the less serious fatty liver disease, especially in light of the potentially serious complica-tions of NAFLD (cirrhosis, HCC).

6.1. Viral hepatitides

Due to the considerable significance that the progression of the disease to liver cirrhosis and HCC has for health policy, patients whose medical histories sug-gest toxic damage should always undergo viral serology testing (see Fig. 4). Although infection with the hepatitis B virus (HBV) has become rarer in patients who grew up in Germany as vaccination has been recommended here for years, approximately 400 million people are infected worldwide. Given the influx of patients from Eastern Europe, the Middle East and Asia, this disease requires continued attention. Worldwide, some 130–170 million people are infected with chronic hepatitis C (HCV), with 3–5 million virus carriers across Europe [16].

In patients with chronic liver disease, viral serology should involve using anti-HCV, anti-HBc and HBsAg to test for HCV and HBV. If the aforementioned screening parameters provide evidence of an HBV infection, further differentiation is nec-essary between anti-HBc IgM as the marker of acute infection and anti-HBc IgG as the marker of chronic infection. HBV DNA and HBcAg levels should also be determined [17]. If a chronic HBV infection is present, HBeAg levels should be de-termined, a hepatitis D (HDV) co-infection should be excluded and abdominal so-nography should be performed at least every 6 months irrespective of any further treatment in order to detect HCC at an early stage. At present, a liver biopsy is indicated less and less often because non-invasive test procedures, e.g. transient elastography (FibroScan®), are available for determining the severity of fibrosis; however a liver biopsy remains valuable in the event of unexplained liver chang-es or before the start of treatment. If there is evidence of anti-HCV, HCV RNA levels and the genotype should be determined, co-infection with HIV exclud- ed and abdominal sonography performed. Here, too, liver biopsy is now only rarely needed for treatment planning; non-invasive fibrosis measurements as a follow-up procedure are just as well established as they are with HBV infection. In immunosuppressed patients, examination for HEV is essential because chronic progression is also possible in these cases [18].

6.2. Non-alcoholic fatty liver disease

The most common chronic liver disease in industrial nations is non-alcoholic fatty liver disease (NAFLD). It affects approximately one third of the population of Europe and may progress to non-alcoholic steatohepatitis (NASH) and liver cirrho-sis with the associated consequences. It is seen as a hepatological manifestation of metabolic syndrome and is commonly associated with insulin resistance. Other potential reasons for the presence of NAFLD are intestinal diseases (celiac disease, IBD), steroid therapy, chemotherapy, parenteral nutrition and severe general ill-nesses (Figs. 11a–b). In contrast to alcoholic damage, programmed cell death (apoptosis) seems to play a decisive role in the pathogenesis of the disease, so that in the future, serum markers for apoptosis (M30) will come to have a diag-nostic value [19, 20]. Along with the dominant ALT elevation, GGT and ferritin are typically also elevated. However, when assessing LFT values in NAFLD, it must be borne in mind that the upper limits of the normal ALT range, as currently defined, have probably been set too high, so that screening with ALT can provide false-neg-ative results when fatty liver disease is suspected. As current studies by our work-ing group attest, a drop in LFT values in patients with risk factors for NAFLD can aid the early detection of chronic liver disease [5, 21]. A specific marker confirm-ing a NAFLD diagnosis does not yet exist, so that the medical history and clinical examination are of central value along with the exclusion of other parenchymal liver diseases.

26

Fig. 11a: LFT values in celiac disease

Celiac disease

Parenchymal damageALT dominant!!

Sonographic:Hepatic steatosis

AST > n–100 U/LALT > n–200 U/L GLDH > n–10 U/L

GGT > n–100 U/LAP > n–100 U/L

T-bilirubin normal

Hepatic steatosis can be clearly shown using sonography, classically in comparison with kidney parenchyma and by means of ultrasound damping distant from the probe; however, assessments of the degree of severity vary greatly between ob-servers, despite the established criteria for sonography. Liver biopsy remains the gold standard for grading and staging of steatosis and for assessing the severity of fibrosis in NAFLD. A new method that is particularly suitable for detecting the early stages of fatty liver disease is the CAP (controlled attenuation parameter) method, which can be determined with modern transient elastography devices [22, 23].

27

Fig. 11b: Diagnostic algorithm for liver disease with celiac disease

Elevated LFT values with a diagnosis of celiac disease

OptimizationTreatment for concomitant

liver diseasemodified after: Rubio-Tapia & Murray. Hepatology. 2007

Transaminases

Responds to a gluten-free diet? Elevated GGT? Normal

Bone disease?

(PTH, Ca, TSH)

Alkaline phosphatase

Yes

Follow-up

No

Compliance?Further diagnostics

necessary: laboratory tests, possibly liver

biopsy

28

6.3. Alcoholic liver disease

Alcohol-toxic liver disease is the second most prevalent chronic liver disease in Germany and typically presents with a higher AST than ALT (= De Ritis ratio > 1) [24], elevated GGT, elevated MCV (mean corpuscular volume) and an ele-vated IgA level. The CDT (carbohydrate-deficient transferrin) level in serum is a helpful parameter if alcohol consumption is assumed but denied by the patient; however, it can also produce false-positives if liver cirrhosis is present or during pregnancy. In our center, we use determination of ethyl glucuronide in the urine or in a hair sample, which can be used to retrospectively determine alcohol con-sumption in the previous 3 months (see Fig. 5).

6.4. Autoimmune liver diseases

Immunological liver diseases are rare but still of considerable importance for diag-nostics, because effective therapy at an early stage can prevent the development of cirrhosis. Therefore, patients should be screened for these diseases if chronic liver diseases of unclear etiology are present.

Autoimmune hepatitis (AIH) is a disease with a genetic predisposition (HLA-B8, -DR3 and -DR4) that occurs predominantly in women (80%) and is associated with elevat-ed transaminase levels, which skyrocket during inflammatory flares and are accom-panied by an early reduction in hepatic synthetic function. Diagnosis is reached once a viral origin has been excluded through evidence of hypergammaglobulinemia, positive autoantibodies (ANA, SMA, LKM or SLA) and typical histological findings (Tab. 6). Other immune-mediated liver diseases which can also occur as a variant syndrome with AIH are primary biliary cholangitis (PBC) and primary sclerosing chol-angitis (PSC), which are classified as cholestatic liver diseases. As regards PBC, over 90% of cases occur in middle-aged women, and the disease is often associated with excruciating pruritus. In addition to elevated cholestasis parameters, IgM levels are typically markedly elevated. Here, too, diagnosis is achieved through evidence of autoantibodies (AMA subtype M2) and the corresponding histology. PSC is a disease of the bile ducts that involves the formation of stenoses and recurrent cholangitis and is often associated with inflammatory bowel diseases. Elevated pANCA titers are found here as autoantibodies. Diagnosis is supported by bile duct imaging. As a non-invasive procedure, magnetic resonance cholangiopancreatography (MRCP) is preferred, with ERCP being used only when findings are unclear or with therapeutic intent. With this disease, there is a high risk of colonic and bile duct neoplasia, which means that regular preventive check-ups should be performed (Fig. 12).

29

Tab. 6

(* Maximale Punktzahl für alle Autoantikörper 2)

AIH criteria ≥ 6: AIH probableAIH criteria ≥ 7: AIH confirmed

Variable Cut-off Points

ANA or SMA ≥ 1:40 1*

ANA or SMA ≥ 1:80 2*

LKM ≥ 1:40 2*

SLA Positive 2*

IgG> upper limit of normal (ULN)> 1.1 time above ULN

12

Liver histologyReconcilable with AIHTypical for AIH

12

Exclusion of viral hepatitis Yes 2

Fig. 12: PBC and PSC

Primary biliary cholangitis

GGT and AP dominant!!

AMA subtype M2IgM

Primary sclerosing cholangitis

pANCA

GLDH> 10–100 U/L

GGT >100–1000 U/LAP >100–300 U/L

T-bilirubin > n–5 mg/dL

GGT > 100–300 U/LAP > 100–300 U/L

T-bilirubin > n–3 mg/dL

6.5. Metabolic liver diseases

In the presence of unexplained chronic liver diseases, differential diagnosis should consider rare metabolic diseases affecting the liver, especially if the patient has relatives with these diseases. Among these diseases are Wilson‘s disease, hemo-chromatosis and a1-antitrypsin deficiency. Wilson‘s disease is a disease affecting copper storage, which is inherited through an autosomal recessive gene muta-tion and which manifests itself at an early stage with neurological dysfunction and liver disease progression. If the presence of this disease is suspected, it is important to determine copper levels in urine collected over 24 hours. The de-termination of ceruloplasmin in serum may be helpful, but can show falsely low values, even in acute infections or cirrhotic liver diseases.

Hemochromatosis is the most common liver disease caused by a congenital metabolic defect (in Europe 1:1000, M:F = 10:1). This condition features iron overload in the parenchyma of various organs, which may lead clinically to hepa-topathy, arthropathy, diabetes and other endocrinopathies as well as cardiac insufficiency and neurological symptoms. Evidence of hyperglobulia, elevated serum iron, ferritin and transferrin saturation is an indication of this disease. In classic hemochromatosis, over 90% of patients are homozygous for the C282Y mutation in the HFE gene, although manifest hemochromatosis develops in only 25% of homozygotes.

An a1-antitrypsin deficiency presents clinically with a cholestatic liver disease be-fore the age of 60. Diagnosis can be made on the basis of the determination of a1-antitrypsin in serum – a genetic test is not necessary for screening.

6.6. Lysosomal storage diseases 6.6.1. Gaucher‘s disease

Gaucher‘s disease is a congenital lysosomal storage disorder, in which the lipid substance known as glucocerebroside is not metabolized effectively. So-called Gaucher cells can generally be detected in the spleen, liver and bone marrow, and occasionally in the lungs. These organs also represent the sites at which Gaucher’s disease is most likely to present. Gaucher‘s disease has a chronic progression marked by hepatosplenomegaly, hematological changes (anemia, thrombocytopenia), bone involvement and sometimes neurological symptoms. The onset of the disease and the severity of clinical symptoms vary considerably. Even in early childhood, splenomegaly may be present, which leads to hyper-splenism with anemia as well as to leukocytopenia and thrombocytopenia. It is particularly important to rule out Gaucher‘s disease in patients from Turkey or the Arab region who present with unexplained hepatopathies.

30

31

6.6.2. Lysosomal acid lipase deficiency

A congenital lysosomal acid lipase deficiency (LAL-D) is among the lysosomal storage diseases.

It is also known as Wolman disease in the first months of life and as cholesteryl ester storage disease (CESD) in children and adults. Today, these different mani-festations of LAL-D are grouped together as an independent disease which can present in all age groups [25].

Because the clinical manifestations vary significantly depending on when the disease first appears, training is necessary to develop an awareness of LAL-D, and especially of its clinical symptoms and diagnostics. Modern methods make it possible to diagnose adult patients in particular even during the “silent” stage of the disease. This becomes significant in terms of the comorbidities and mortality rate of LAL-D, which can be reduced through new and supportive therapies.

LAL-D is an autosomal recessive inherited disease resulting from a homozygous or compound heterozygous mutation of the LIPA gene (lipase A, lysosomal acid, cholesterol esterase). The mutation leads to the reduction or complete elimina-tion of LAL enzyme activity. The severity of symptoms and age at which they present vary depending on the manifestation. As a result of a mutation, these lipids accumulate in hepatocytes and macrophages in the spleen, the gastroin-testinal tract or in blood vessels. In the long term, this pathological accumulation leads to organ damage [26]. The spectrum of clinical manifestations ranges from dyslipidemia (pathological LDL/HDL ratio) and hepatic dysfunction through hepa-to- and/or splenomegaly, persistently elevated transaminase levels and microve-sicular steatosis to fibrosis and cirrhosis. Less common diseases such as LAL-D should be considered as a differential diagnosis and be ruled out diagnostical-ly, especially if symptoms do not clearly correspond to the disease profiles of NAFLD/NASH.

6.7. Less common causes

Lastly, a variety of infectious diseases generally cause transient elevation of transaminase levels. There are also several infectious diseases which occur rare-ly in Germany but which should be considered in foreign patients or travelers from abroad (Tab. 7).

32

Infectious diseases involving the liver

Bacteria Pneumococci, staphylococci, streptococci, gonococci, clostridia, E. coli, salmonel-lae, brucellae, tuberculosis, leptospirosis, syphilis

Fungi Histoplasmosis, actinomycosis

ParasitesAmoebas, malaria, trypanosoma, toxoplasma

HelminthsEchinococcus granulosus, Echinococcus multilocularis, ascarids, schistosomiasis, Fasciola hepatica

Viruses

CMV, EBV, HSV, HIV, rubella, varicella, yellow fever, Coxsackie virus, adeno-viruses, paramyxoviruses, Lassa virus, Marburg virus, Ebola virus

Tab. 7

33

7. Conclusions for clinical practice

· Basic diagnostics for elevated LFT values should be performed in all cases of acute LFT elevation with rising transaminase levels or signs of liver insufficiency as well as in cases of chronically elevated LFT values (> 6 months).

· Acute liver failure requires quick intensive care clarification and treat-ment, and contact with a transplant center should be made at an early stage.

· Cryptogenic liver diseases are largely autoimmune in origin and require further clarification by means of special biochemical markers and liver biopsy.

· The most common chronic liver disease is non-alcoholic fatty liver disease, which is generally associated with metabolic syndrome.

· Early diagnosis and treatment of chronic liver disease is crucial for preventing the development of liver cirrhosis and hepatocellular carcinoma.

34

Abbreviations

AIH: autoimmune hepatitisALF: acute liver failure ALT: alanine aminotransferase

(corresponds to GPT glutamate-pyruvate transaminase)AMA: anti-mitochondrial antibodiesANA: anti-nuclear antibodiesAP: alkaline phosphataseASH: alcoholic steatohepatitis AST: aspartate aminotransferase

(corresponds to GOT glutamate-oxaloacetate transaminase)BNP: B-type natriuretic peptideCa: calciumCT: computed tomographyERCP: endoscopic retrograde cholangiopancreatographyGGT: gamma-glutamyl transferaseGLDH: glutamate dehydrogenaseHCC: hepatocellular carcinomaINR: international normalized ratioLAL-D: lysosomal acid lipase deficiencyLDH: lactate dehydrogenase LFT: Liver function testLKM: liver-kidney microsomal antibodiesNAFLD: non-alcoholic fatty liver disease NASH: non-alcoholic steatohepatitispANCA: perinuclear anti-neutrophil cytoplasmic antibodiesPBC: primary biliary cholangitisPSC: primary sclerosing cholangitisPTH: parathyroid hormoneSLA: antibodies against soluble liver antigensTA: transaminaseTPN: total parenteral nutritionTSH: thyroid-stimulating hormonePT: prothrombin timeUS: ultrasound/sonography

35

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