NON-ALCOHOLIC FATTY LIVER DISEASE
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it is a disease of affluent societies which increases in prevalence in obesity
It has become the most common cause of chronic liver disease after hepatitis B, hepatitis C and alcohol
It can be classified into simple fatty liver disease or non-alcoholic fatty liver, NAFL
non-alcoholic steatohepatitis NASH
The former has a benign prognosis, but the latter is associated with fibrosis and progression cirrhosis
In NAFLD there is accumulation of fat (fatty infiltration) in the liver cells (hepatocytes)
In NASH, the fat accumulation is associated with varying degrees of inflammation (hepatitis) and scarring (fibrosis) of the liver
Causes
primary
secondary
1diabetes
2the metabolic syndrome, obesity
3tamoxifen, amiodarone , tetracycline, MTX, CS, aspirin, antiviral
4jejunal bypass surgery
5ch HBV, ch HCV
6chronic autoimmune hepatitis (AIH), and Wilson s disease
Pathophysiology
Most individuals with NAFLD have insulin resistance but not necessarily overt glucose intolerance
The current two-hit hypothesis explains why not everyone with fatty liver disease develops hepatic fibrosis
The first hit results in steatosis (fatty liver
‘The second hit’ which is only complicated by inflammation Leptin , which, as well as reducing appetite, is fibrogenic in vitro, is probably then needed to cause hepatic fibrosis
The components of the first hit include release of free fatty acids from central adipose tissue, which, along with adipokines, drain into the portal vein as well as causing insulin resistance. Together, these processes result in reduced hepatic fatty acid oxidation and increased fatty acid synthesis
Clinical features
Most patients present with asymptomatic abnormal LFTs, particularly elevation of the transaminases or isolated elevation of the GGT
Occasionally, the condition presents with a complication of cirrhosis such as variceal haemorrhage or hepatocellular carcinoma
In contrast to alcoholic liver disease, jaundice only occurs when cirrhosis is established
NAFLD is the most likely diagnosis in a patient with mild to moderately elevated serum transaminases, no history of alcohol abuse and a negative chronic liver disease screen
Fatigue and malaise , A dull pain in the upper right portion of the abdomen , Loss of appetite , Weakness , Weight loss, Nausea and vomiting
Investigations
Liver function tests
Unfortunately, there is no single diagnostic blood test but, in contrast to alcoholic liver disease, the ALT is normally higher than the AST. Elevated ALP levels are seen in about 30% of cases. It is important to differentiate NAFL, which does not require follow-up, from NASH. Elevated serum transaminases greater than twice the upper limit of normal and the presence of the metabolic syndrome are useful predictors of NASH
Ultrasound cannot differentiate NAFL from NASH; in both cases the liver will appear bright on
Liver biopsy
Individuals with serum transaminases greater than twice the upper limit of normal and features of the metabolic syndrome should be offered a liver biopsy to determine whether inflammation and fibrosis are present
Histologically, fat deposition is usually macrovesicular , in contrast to the microvesicular fat seen in acute fatty liver disease of pregnancy. NASH is characterised by fat, Mallory bodies, neutrophil infiltration and pericellular fibrosis. These features are indistinguishable histologically from alcoholic hepatitis, so a diagnosis of NASH relies on excluding alcohol misuse, the absence of jaundice, and the presence of risk factors such as obesity and diabetes
Management
Current treatments are aimed at reducing BMI and insulin resistance
Metformin has been shown to improve LFTs and should be the first-line treatment in type 2 diabetes with NAFLD
Metformin can be used safely in patients with cirrhosis who have good liver function
Thiazolidinediones such as pioglitazone also improve LFTs in NAFLD and early data suggest they may improve inflammation and fibrosis
Weight loss will also reduce serum transaminase levels, improve liver fibrosis and reduce insulin resistance, IN 80%
Antioxidants such as vitamin E & C are not effective
There is no evidence that HMG-CoA reductase inhibitors (statins) are of value in the treatment of NAFLD but they are not contraindicated for treatment of coexistent hyperlipidaemia
ursodeoxycholic acid have little benefit
The role of anti-obesity (bariatric) surgery in patients with morbid obesity and NAFLD can result in improvement in liver fibrosis
Ongoing research is revealing a possible link between obstructive sleep apnea and NAFLD/NASH. Studies are ongoing to evaluate if the treatment of obstructive sleep apnea results in the improvement of fatty liver disease
The novel therapy of using N –acetylcysteine and cannabinoid blockers is also being explored in animal studies
Hepatocellular carcinoma can complicate NAFLD cirrhosis. Although fewer than 5% of liver transplants are currently performed for NAFLD, this is likely to increase. Unfortunately, the condition may recur in the graft
Haemochromatosis
it is a condition in which the amount of total body iron is increased; the excess iron is deposited in, and causes damage to, several organs, including the liver
It may be primary or secondary to other diseases
Causes
Primary haemochromatosis
Hereditary haemochromatosis
Congenital acaeruloplasminaemia
Congenital atransferrinaemia
Secondary iron overload
Parenteral iron-loading (e.g. repeated blood transfusion)
Iron-loading anaemia (thalassaemia, sideroblastic anaemia, pyruvate kinase deficiency)
Liver disease
Complex iron overload
Juvenile haemochromatosis
Neonatal haemochromatosis
Alcoholic liver disease
Porphyria cutanea tarda
African iron overload (Bantu siderosis)
In hereditary haemochromatosis (HHC) iron is deposited throughout the body and total body iron may reach 20-60 g (normally 4 g)
The important organs involved are the liver, pancreatic islets, endocrine glands and heart
In the liver, iron deposition occurs first in the periportal hepatocytes, extending later to all hepatocytes
The gradual development of fibrous septa leads to the formation of irregular nodules, and finally regeneration results in macronodular cirrhosis
An excess of liver iron can occur in alcoholic cirrhosis but this is mild by comparison with haemochromatosis
pathophysiology
The disease is caused by increased absorption of dietary iron and is inherited as an autosomal recessive trait. Approximately 90% of patients are homozygous for a single-point mutation resulting in a cysteine to tyrosine substitution at position 282 (C282Y)
Fewer than 50% of C282Y homozygotes will develop clinical features of haemochromatosis; therefore other factors must also be important
HHC may promote accelerated liver disease in patients with alcohol excess or hepatitis C infection
Iron loss in menstruation and pregnancy protects females from developing clinical manifestations of HHC, as 90% of patients are male
Clinical features
Symptomatic disease usually presents in men over 40 years with features of liver disease
often with hepatomegaly, diabetes mellitus or heart failure,Fatigue and arthropathy are early symptoms
Leaden-grey skin pigmentation due to excess melanin occurs, especially in exposed parts, axillae, groins and genitalia; hence the term bronzed diabetes
Impotence, loss of libido, testicular atrophy and arthritis with chondrocalcinosis secondary to calcium pyrophosphate deposition are also common
Cardiac failure or cardiac dysrhythmia may occur due to iron deposition in the heart
Investigations
a greatly increased ferritin, a raised plasma iron and saturated plasma iron-binding capacity
Transferrin saturation > 45% is suggestive of iron overloadSignificant liver disease is unusual in patients with ferritin < 1000 ?g/L
MRI has high specificity for iron overload, but poor sensitivity
Liver biopsy allows assessment of fibrosis and distribution of iron (hepatocyte iron characteristic of haemochromatosis)
The Hepatic Iron Index (HII) provides quantification of liver iron (?mol of iron per g dry weight of liver/age in years). HII > 1.9 suggests genetic haemochromatosis
management
Treatment consists of weekly venesection of 500 mL blood (250 mg iron) until the serum iron is normal; this may take 2 years or moreThe aim is to reduce ferritin to < 50 ?g/L. Liver and cardiac problems improve after iron removal, but joint pain is less predictable and can improve or worsen after iron removal. Diabetes mellitus does not resolve after venesection
First-degree family members should be investigated, preferably by genetic screening and also by checking the plasma ferritin and iron-binding saturation
Liver biopsy is only indicated in asymptomatic relatives if the LFTs are abnormal and/or the serum ferritin is greater than 1000 ?g/L because these features are associated with significant fibrosis or cirrhosis. Asymptomatic disease should also be treated by venesection until the serum ferritin is normal
Pre-cirrhotic patients with HHC have a normal life expectancy, and even cirrhotic patients have a good prognosis, compared with other forms of cirrhosis
Screening for hepatocellular carcinoma is mandatory because this is the main cause of death, affecting about one-third of patients with cirrhosis irrespective of therapy
Venesection reduces but does not abolish the risk of hepatocellular carcinoma in the presence of cirrhosis
Secondary haemochromatosis
Many conditions, including chronic haemolytic disorders, sideroblastic anaemia, other conditions requiring multiple blood transfusion (generally over 50 L), porphyria cutanea tarda, dietary iron overload and occasionally alcoholic cirrhosis, are associated with widespread secondary siderosis
The features are similar to primary haemochromatosis, but the history and clinical findings point to the true diagnosis
Wilson s disease
Wilson s disease (hepatolenticular degeneration) is a rare but important autosomal recessive disorder of copper metabolism that is caused by a variety of mutations in the ATP7B gene on chromosome 13
Total body copper is increased, with excess copper deposited in, and causing damage to, several organs
Pathophysiology
Normally, dietary copper is absorbed from the stomach and proximal small intestine and is rapidly taken into the liver, where it is stored and incorporated into caeruloplasmin, which is secreted into the blood
The accumulation of excessive copper in the body is ultimately prevented by its excretion, the most important route being via the bile. In Wilson s disease, there is almost always a failure of synthesis of caeruloplasmin; however, some 5% of patients have a normal circulating caeruloplasmin concentration and this is not the primary pathogenic defect
the organs most affected are the liver, basal ganglia of the brain, eyes, kidneys and skeleton
Clinical features
Symptoms usually arise between the ages of 5 and 45 years
Hepatic disease occurs predominantly in childhood and early adolescence, although it can present in adults in their fifties
Neurological damage causes basal ganglion syndromes and dementia which tends to present in later adolescence. These features can occur alone or simultaneously
Other manifestations include renal tubular damage and osteoporosis, but these are rarely presenting features
Liver disease
Episodes of acute hepatitis, sometimes recurrent, can occur, especially in children, and may progress to acute fulminant liver failure. Caused by the liberation of free copper into the blood stream, causing massive haemolysis and renal tubulopathy
Chronic hepatitis can also develop insidiously and eventually present with established cirrhosis; liver failure and portal hypertension may supervene
Recurrent acute hepatitis of unknown cause, especially when accompanied by haemolysis, or chronic liver disease of unknown cause in a patient under 40 years old suggests Wilson s disease
Neurological disease
Clinical features include a variety of extrapyramidal features, particularly tremor, choreoathetosis, dystonia, parkinsonism and dementia
Unusual clumsiness for age may be an early symptom
Kayser-Fleischer rings
These are the most important single clinical clue to the diagnosis and can be seen in 60% of adults with Wilson s disease (less often in children but almost always in neurological Wilson s disease), seen only by slit-lamp examination
Kayser-Fleischer rings are characterised by greenish-brown discoloration of the corneal margin appearing first at the upper periphery They eventually disappear with treatment
Investigations
A low serum caeruloplasmin is the best single laboratory clue to the diagnosis
However, advanced liver failure from any cause can reduce the serum caeruloplasmin, and occasionally it is normal in Wilson s disease
Other features include a high free serum copper concentration, a high urine copper excretion of greater than 0.6 ?mol/24 hrs (38 ?g/24 hrs) and a very high hepatic copper content
Measuring 24-hour urinary copper excretion whilst giving D-penicillamine is a useful confirmatory test; more than 25 ?mol/24 hrs is considered diagnostic of Wilson s disease
Genetic testing may be useful in screening families once the abnormality has been identified in an affected individual
Management
The copper-binding agent, penicillamine, is the drug of choice, 1.5 g/day (range 1-4 g). The dose can be reduced once the disease is in remission but treatment must continue for life, even through pregnancy
Abrupt discontinuation of treatment must be avoided because this may precipitate acute liver failure
Toxic effects occur in one-third of patients and include rashes, protein-losing nephropathy, lupus-like syndrome and bone marrow depression. If these do occur, trientine dihydrochloride (1.2-2.4 g/day) and zinc (50 mg 8-hourly) are alternative effective therapies
Liver transplantation is indicated for fulminant liver failure or for advanced cirrhosis with liver failure
The prognosis is excellent, provided treatment is started before there is irreversible damage
Siblings and children of patients with Wilson s disease must be investigated and treatment should be given to all affected individuals, even if they are asymptomatic
Clinical features
There are no stigmata of chronic liver disease other than jaundice. Increased excretion of bilirubin and hence stercobilinogen leads to normal-coloured or dark stools, and increased urobilinogen excretion causes the urine to turn dark on standing as urobilin is formed. In the presence of haemolysis, pallor due to anaemia and splenomegaly due to excessive reticulo-endothelial activity are usually present
Investigations
In Gilbert s syndrome the plasma bilirubin is usually less than 100 ?mol/L (?6 mg/dL) and the LFTs are otherwise normal. There is no bilirubinuria because the hyperbilirubinaemia is predominantly unconjugated. Other LFTs and hepatic histology are normal. The condition has an excellent prognosis, needs no treatment, and is clinically important only because it may be mistaken for more serious liver disease