Auto Immune Hypokalemia?? Dr Dheda : Grey's Department of ...

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Auto Immune Hypokalemia???Auto Immune Hypokalemia???

Dr S DhedaDr S DhedaGreys Hospital, Department of Greys Hospital, Department of

Medicine, PMBMedicine, PMBGrand round presentationGrand round presentation

Our Patient:• Mrs BD• 68yr old female patient• Presented to medical outpatient clinic in April with:

– Polyuria– Polydipsia– Generalised weakness– Weight loss– Five months duration of symptoms

– No headaches or visual disturbances– No burning on micturition, No diarrhoea– No over the counter or traditional medication

Past medical History:– Seen at MOPD five months prior with a main

complaint of weakness and weight loss– Thyroid function test done and was found to be

hypothyroid – Supplemented with Eltroxin, with some

improvement of symptoms– No history of Diabetes, Hypertension, tuberculosis– No prior hospital admissions

Drug History:• Eltroxin 0.025mcg daily started five months prior• Ciprofloxacin for possible urinary tract infection –

with no change in symptoms

Social History:• No history of Alcohol, smoking, recreational drugs

Family History:• Nil of note

Allergies:• Penicillin

Occupational History:• Previously employed at shoe factory

On Examination:• Stable and comfortable on admission• Vital signs:

– Blood pressure: 110/70mmHg– Pulse: 76 bpm, regular, no delays– Temperature: 37 degrees

• General examination:– Not ill looking– No pallor, No clubbing, Not jaundiced, Not

dehydrated, No peripheral oedema

• Chest:- Clear

• Cardiovascular:– Not in cardiac failure, heart sounds clear, No

murmurs

• Abdomen:– Soft, non tender, No masses or organomegaly– Bowel sounds present

• Nervous system:– No focal signs, power 5/5 globally, No

meningism, – Fully orientated– No cranial nerve lesions, normal visual fields

and acuity

• Blood results from MOPD:

Electrolytes and Liver function tests: Na+ - 143 CO2 - 18Cl- - 118 Urea - 4.5K+ - 3.24 Cr - 85

Anion Gap - 9.9

Total prot - 92 γGT - 17Albumin - 43 ALP - 78Total Bil - 19 ALT - 28

Thyroid Function testsT4 - 10.39 (12 – 22)TSH - 6.58 (0.27 – 4.2)Anti peroxidase Ab- 116 iu/ml (5 – 36)

Cortisol 584.1 nmol/l (171 – 536)

ESR: 65mm/hr

Fasting Glucose 3.8mmol/l

After reviewing these results and with persistence of symptoms, patient was admitted for further investigations

Differential Diagnosis at this point:

- Diabetes insipidus- Psychogenic polydipsia- Diabetes mellitus less likely in view of fasting sugar

Bloods results on day of admission:FBC:Hb - 12.3 Plt - 283 WCC - 5.9MCV - 80.6 MCH - 26.5

U+E:Na - 141 K+ - 2.39 AG – 6.9Cl - 120 CO2 - 17Ur - 4.6 Cr - 94

LFT:ALP - 89 TBil - 15TP - 84 Alb - 38γGT - 18 ALT - 33

Measured Osmolality 303mosm/kg

Arterial Blood gas:pH - 7.37 PCO2 - 3.62PO2 - 13.76 HCO3 - 15.2

Urine Ph (formal): 8,0

• K+ was intravenously replaced in ward and supplemented orally

In Summary:

• 68yr old female patient with antibody positive hypothyroidism presenting with polyuria, polydipsiaand weight loss of 5/12 duration and presenting with hypokalemia with associated hyperchloremic, normal AG metabolic acidosis

Causes of Hyperchloraemic Metabloic Acidosis:

Renal1. Proximal tubule dysfunction (Type II RTA) 2. Distal tubule dysfunction (Type I RTA) 3. Hypoaldosteronism ("Type IV RTA")

Other renal: 4. Carbonic anhydrase inhibitors (resembles Type II

RTA) 5. Primary hyperparathyroidism (resembles Type II

RTA) 6. Drugs: pentamidine, non-steroidal anti-

inflammatories, cyclosporine

.

Non Renal:• Gastrointestinal bicarbonate loss:

related to diarrhoea, or pancreatic loss of bicarbonate; Ureterosigmoidostomy

• Iatrogenic: Administration of:• Large amounts of phosphate • Cation exchange resins • Calcium chloride • cholestryamine

In view of:• Presenting symptoms:

– Weakness– Polyuria– Polydipsia– LOA and weight loss

• Hyperchloraemic Normal Anion Gap Metabolic Acidosis

• Hypokalemia• Urine pH of 8,0 in setting of Metabolic Acidosis

A diagnosis of Type 1 Renal Tubular Acidosis was made

Renal Tubular Acidosis:

• Disorder of renal acidification

• Characterised by a hyperchloraemic normal Anion Gap (AG) Metabolic acidosis

• 3 major forms exist

• Type 1 – Distal

• Type 2 – Proximal

• (Type 3 – Mixture of type 1 and 2)

• Type 4 – Aldosterone resistance/decreased aldosterone

Causes:• Genetic AD, AR• Haematological diseases:

• sickle cell disease• heriditary elliptocytosis• Multiple Myeloma

• Autoimminue diseases • Sjogren’s syndrome• SLE• thyroiditis• CAH

• Disorders which cause nephrocalcinosis• primary hyperparathyroidism• vitamin D intoxication

• Drugs or toxins• amphotericin B

• Lithium

• obstructive uropathy

• Chronic pyelonephritis

• Diabetes Mellitus (IV)

• Hypertensive Nephrosclerosis (IV)

Type 1 Distal RTA:

• An inability to secrete H+ ions into the distal tubule

• urine pH remains > 5.5 despite serum acidaemia

Pathophysiological Mechanisms in Reduced H+ Secretion in Distal Tubule

• "Weak pump" - Inability for H+ pump to pump against a high H+ gradient

• "Leaky membrane" - Back-diffusion of H+ [eg This occurs in RTA due to amphotericin B]

• "Low pump capacity" - Insufficient distal H+ pumping capacity due to tubular damage.

Chronic acidosis results in ↓Ca reabsorption, together with the bone buffering of the metabolic acidosis results in hypercalciuria

Typical Findings:an inappropriately high urine pH (usually > 5.5)

low acid secretion and urinary bicarbonate excretion

Metabolic acidosis

Hypercalciuria - Nephrocalcinosis

- Ca PO4 stones

Hypokalemia

Polyuria

No Bicarbonaturia

Renal sodium wasting is common and results in depletion of ECF volume and secondary hyperaldosteronism with increased loss of K+ in the urine.

• Treatment with sodium citrate (Shohls solution) corrects the Na+ deficit, restores the extracellular fluid volume and results in correction of the hypokalaemia.

• Potassium Alkali salts can be used if hypokalemia is peristent

Type 2 Proximal RTA:

• Usually occurs as as part of a generalised disorder of proxmal tubular function

• proximal tubular wasting of bicarbonate diminished bicarbonate resorption results in loss of bicarbonate in the urine Inappropriate bicarbonate loss

TYPE 4 RTA:

• Generalised distal tubular dysfunction

• Aldosterone resistance or Absence

• Distal tubule secretion of H+ and K+ is abnormal resulting in metabolic acidosis with hyperkalemia

• Urinary acidification is normal (pH can drop below 5).

<10>15<10% filtered HCO3excreted

HighLowLowSerum K+

No

Low

<5.5

Type 4

No

<5.5

Normal

<5.5

Type 2

> 5.5Urine pH afterAcid Loading test

LowDaily acid excretion

YesStones/Nephrocalcinosis

>5.5Urine PH

Type 1Differentiating RTA:

• Our patient was supplemented with Shohls solution and oral K+ replacement

• Repeat Electrolytes:

Na - 142 K+ - 4.12Cl - 108 C02 - 26.6Urea - 2.3 Creat - 77AG - 11

• She reported dramatic improvement in her symptoms with resolution of her polyuria, polydipsia and weakness

On further questioning:No bone pain, No history of any of the drugs in questionShe complained of occasional dry eyes and a persistent ‘itchy’ sensationTogether with a feeling of dryness in her mouthA new found craving for bananasNo dysphagiaNo rashesNo photosensitivityNo joint painsNo chest pains

Referred to the Ophthalmologist

Schirmers Test (+) showing decreased tear secretion

(Rose Bengal solution test not done)

Further investigations revealed:

Anti nuclear antibodies (+)Significant titre of 1:800

With Hep2 cells staining showing a speckled patternENA’s were positive– Anti SS-A (Ro) and Anti SS-B (La)

Anti DNA Ab (-)Parietal cell Ab (-)LKM Ab (-)Mitochondrial Ab (-)Rnp Ab (-)Anti Sm Ab (-)

HENCE:A Diagnosis of Sjogren’s Syndromewas made and our patient is awaiting Renal Biopsy

SJOGREN’S SYNDROME

• slowly progressive, inflammatory autoimmune disease affecting primarily the exocrine glands.

• Histologically, it is characterised by lymphocytic infiltrates replacing functional epithelium and leading to decreased exocrine secretions.

• Serologically, Ro and La autoantibodies are present.

• all ages, but it affects primarily females during the fourth and fifth decades of life with a female:male ratio of 9:1.

• In rheumatology clinics approximately 30% of rheumatoid arthritis (RA) and scleroderma patients have at least histologic evidence of Sjogren's syndrome.

• Patients present with symptoms related to decreased exocrine function

• Primarily decreased lacrimal and salivary gland activity

Renal Involvement • Most patients present with:• hypokalemic, hyperchloremic distal renal

tubular acidosis • 2’ to interstitial infiltration and destruction

by lymphocytes. • renal stones, nephrocalcinosis • May have proximal tubular acidosis with

Fanconi's syndrome • Renal biopsy:

– interstitial lymphocytic infiltration. – Membranous or membranoproliferative

glomerulonephritis • Hypocomplementemia

Autoimmune Thyroid Disease • A high percentage of patients present with

anti-thyroid antibodies and signs of hypothyroidism

Revised international Classification Criteria for Sjogren’s Syndrome:

I. Ocular SymptomsII. Oral symptomsIII.Ocular signs (objective)IV. HistopathologyV. Salivary Gland involvement (objective)VI. Antibodies

(3 from III, IV, V, VI)(4 of the 6 as long as either IV or IV present)

THANK YOU

Patterns of staining on Hep 2 cells:• Speckled

– Nonspecific – Most common pattern – Pattern occurs doe to antibodies directed against ENA’s

• Diffuse/homogeneous – Nonspecific – Second most common pattern – Pattern occurs due to antibodies directed against histone

• Rim/peripheral – Specific for SLE – Pattern occurs due to antibodies directed against DNA

Centromere – Specific for CREST (Limited Systemic Sclerosis) – Pattern occurs due to antibodies directed against

centromere• -Nucleolar

– Relatively specific for Scleroderma/Diffuse SS– Pattern occurs due to antibodies directed against nucleoli

• The defective proximal tubule cannot reabsorb the filtered load (of HCO3) and the distal delivery of bicarbonate is greatly increased, overcoming the DCT reabsorptive capacity

• This HCO3 loss continues resulting in the Metabolic acidosis, until

• until the serum bicarbonate level drops to a level where equilibrium is reached (usually at about 15-17 mmol/l).

• Thereafter the DCT can now handle the decreased HCO3 load with normal urinary acidificaction

• Hence differentiation can easily be made by measuring urine pH levels

Treatment: • Orally administered alkali, however may require large

amounts because HCO3 is rapidly lost in urine• May also need K+ supplementation

Treatment:• Low K+ diet• Mineralocorticoid replcement• Loop diuretic• Exchange resins

Ocular Involvement.

• Diminished tear production leads to keratoconjunctivitis sicca (KCS)

• patients usually complain of a burning foreign body sensation, a sandy or scratchy sensation under the lids, itchiness, redness and photosensitivity.

Oropharyngeal Involvement. • difficulty swallowing dry food, inability to speak

continuously, changes in sense of taste, a burring sensation in the mouth, an increase in dental caries and problems in wearing complete dentures.

• Parotid or major salivary gland enlargement occurs in 60% of primary Sjo'gren's syndrome

• Other Organ Involvement. Dryness may affect the upper respiratory tract and oropharynx and cause:– hoarseness, – recurrent bronchitis – pneumonitis.

• Loss of exocrine function:– loss of pancreatic function – hypochlorhydria.

Extraglandular Manifestations • Systemic manifestations include• general constitutional symptoms

– easy fatigability– low grade fever– myalgias and arthalgias

Arthritis. • 50% of primary Sjogren's syndrome patients

experience episodes of arthritis during the course of their disease.

• Articular signs and symptoms include: – arthralgias, – morning stiffness, – intermittent synovitis and – chronic polyarthritis,

Raynauds Phenomenon. • Raynaud's phenomenon occurs in 35% of

primary Sjogren's syndrome usually • present with swollen hands, but in contrast to

scleroderma they do not develop telangiectasias or digital ulcers.

Pulmonary Involvement. • frequent but rarely clinically important. • can present either with • dry cough secondary to dryness of

tracheobronchial mucosa (xerotrachea) or • dyspnea from interstitial lung disease.

Gastrointestinal and Hepatobiliary Features • Dysphagia, due to

– dryness of the pharynx and esophagus or to – abnormal esophageal motility.

• chronic atrophic gastritis and lymphocytic infiltrates, elevated serum gastrin, low levels of serum vitamin B12 and antibodies to parietal cells.

• Acute or chronic pancreatitis• Liver disease

– hepatomegaly (25-28%), – elevated alkaline phosphatase levels (25-

33%) – antimitochondrial antibodies– chronic inflammation of the intrahepatic bile

ducts

Vasculitis:• small and medium-sized vessels • purpura, recurrent urticaria, skin ulcerations and

mononeuritis multiplex

Neuromuscular Involvement:• peripheral sensorimotor neuropathy 2’ to small

vessel vasculitis• Cranial neuropathy

Lymphoproliferative Disease • Increased risk of developing lymphoma • primarily of B cell origin, expressing usually IgM

kappa immunoglobulin

Secondary Sjogren's Syndrome • Approximately 5% of RA patients have clinically

overt symptoms of Sjogrens • diagnosis of RA usually precedes the diagnosis

of Sjogren's syndrome by many years• symptoms are primarily KCS. Parotid or other

major gland enlargement, as well as extraglandular features of Sjogren's syndrome, including lymphadenopathy and renal involvement, are quite uncommon in Sjogren's syndrome associated with RA

Lab investigations:• mild anemia of chronic disease, • elevated erythrocyte sedi-mentation rate • antinuclear antibodies• rheumatoid factors • multiple organ-specific antibodies including

antigastric parietal cell, – Thyroid antibodies, – mitochondrial, – smooth muscle and – salivary duct antibodies.

• Antibodies to Ro(SS-A), La(SS-B)