NASH

المرحلة الرابعة

باطنية

العدد2

15\2\2018

Non-alcoholic fatty liver disease (NAFLD)

د.خلدون ذنون-المرحلة الرلبعة-الطب الباطني
Prevalence increases with obesity and is related to metabolic syndrome and diabetes mellitus.
Common cause of chronic liver disease after hepatitis B.
Rare causes: tamoxifen, amiodarone, jejunal bypass surgery.
Classified into: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).
Pathophysiology:
increased fat import into hepatocytes and reduced fat export.
Insulin resistance
Steatosis , increased TNF, oxidant stress, endotoxin, lead to inflammation and with leptin results in fibrosis.
Clinical picture
Mostly asymptomatic with increase in liver enzymes.
Features of liver cirrhosis and its complications.
Suspected in patients with increased liver enzymes with no history of alcohol intake or chronic liver disease.


Investigations
Liver function tests: ALT higher than AST. 30% increase in ALP.
Sonogram: bright liver
Liver biopsy: indicated if a patient with metabolic syndrome has increase of AST, ALT more than twice upper normal limit.
Histopathology: in NAFL shows macrovesicular fatty liver in pregnancy it is microvesicular. In NASH there is fat deposition in hepatocytes with Mallorys bodies, neutrophils and later fibrosis similar to alcoholism

Management

Reduce body weight (diet, exercise, surgery)
Metformin is the first line drug for diabetics with NAFLD, pioglitazone is a good alternative. Statins no evidence of benefit.
Liver transplant in advanced cirrhosis. 5 year survival is 90%. Disease may recur in the graft. Liver cancer may complicate cirrhosis.

Haemochromatosis

Increased total body iron, iron deposits in liver, heart, pancreas, endocrine glands and other organs.
Primary (hereditary): autosomaol recessive,
Secondary (acquired): blood transfusion, thalassaemia, sideroblastic anemia, alcoholic liver disease and porphyria.

Pathophysiology of primary H.

Normal iron stores 4grams, due to increased dietary iron absorption it reaches between 20-60 gm.
Iron deposits in hepatocytes causes inflammatory hepatitis, fibrosis and later macronodular cirrhosis.
Inheritance of mutant HFE gene on chromosome 6, 90% homozygous, cysteine-tyrosine substitution at position 282 (C282Y) in the HFE protein.
90% are males. Females are protected by menstruation and pregnancy.


Clinical features
Usually men are affected over 40y.
Early features: fatigue and arthropathy.
Later: features of liver disease, hepatomegaly, diabetes, heart failure, arrhythmias,
Leaden grayish skin (bronzed diabetes) due to excess melanin.
Impotence, loss of libido, testicular atrophy
Arthritis, chondrocalcinosis (calcium pyrophosphate).

Investigations

Increased plasma iron, increased serum ferritin, increased saturated plasma iron binding capacity, transferrin saturation > 45%.
MRI specific but not sensitive.
Liver biopsy and estimation of hepatic iron index ((mol iron/1 gm of liver/ age-year) >1.9 is suggestive.
Genetic testing: C282Y and H63D mutation.

Management

Weekly 500ml venesection contains 250 mg iron. Aiming to reduce ferritin <50(gm/L.
Continue venesection as required to keep normal ferritin.
Venesection improves liver and heart function but joint pain is less predictable, and diabetes does not resolve.
Treat diabetes and established cirrhosis.
First degree relatives need genetic screening, plasma ferritin and iron saturation.


Prognosis
Pre-cirrhotic patients: normal life expectancy.
Cirrhotic patients: good prognosis.
Screen for liver cancer as it is the main cause of death, affects 1/3 of cirrhotics even with therapy.

Wilsons disease

Also called (hepatolenticular degeneration), rare autosomal recessive disease, disorder of copper metabolism.
Copper deposition in various organs.

Pathophysiology
Normally dietary copper is absorbed from stomach and proximal small intestine, stored in the liver and incorporated into caeruloplasmin which is secreted into the blood. Excess copper is secreted via bile.
Wilsons disease: failure of caeruloplasmin synthesis, copper deposits in liver, basal ganglia, brain, eyes, kidneys and skeleton.
Mutation in ATP7B gene on chromosome 13 (about 200 mutations).

Clinical features

Symptoms between 5-45 years.
Liver disease: mainly in children and early adolescence.
Later adolescence: basal ganglia lesion and dementia.
Renal tubular damage and osteoporosis.
Liver disease: acute hepatitis may progress to liver failure.
Fulminant liver failure is associated with massive hemolysis and renal tubular damage.
Chronic hepatitis leads to cirrhosis and liver failure.
Neurological
Extrapyramidal : tremor, choreoathetosis, dystonia, parkinsonism.
Dementia
Kayser-Fleischer rings: always present in neurological Wilson disease, occur 60% in adults and less in children. Appear as greenish-brown pigmentation of the corneal margin, disappear with treatment.


Investigations
Low serum caeruloplasmin but occasionally normal.
High free serum copper.
High urine copper excretion.
Liver biopsy: high hepatic copper
Urine copper excretion > 25 (mol/24 hour urine after D-penicillamine is diagnostic.

Management

Penicillamine is the drug of choice (1-4gm/day). Decrease the dose during remission and maintain for life even during pregnancy.
Penicillamine is toxic: rash, proteinuria, SLE, bone marrow depression
Trientine dihydrochloride and zinc are good alternative in case of Penicillamine toxicity.
Liver transplant for fulminant hepatic failure and advanced cirrhosis.
Screen siblings and children of patients and give treatment even for asymptomatic patient.

Prognosis

Excellent if treatment is started early.

Alpha 1 antitrypsin deficiency ((1 ATD)

Autosomal recessive inheritance
(1 AT is a serine protease inhibitor produced by the liver
Mutated form of (1 AT cannot be secreted into the blood by the liver.
Homozygous form (PiZZ) has low plasma (1 AT.
Causes cholestatic neonatal hepatitis which may resolve spontaneously.
In adults leads to chronic hepatitis, cirrhosis and liver cancer.
It leads to early onset severe emphysema.
Diagnosis: low (1 AT, genotyping, liver histopathology shows accumulation of PAS granules in hepatocytes.
Therapy: non specific, abandon cigarette smoking.










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