PORTOSYSTEMIC ENCEPHALOPATHY Dr Arun R Nair Dept of

PORTOSYSTEMIC ENCEPHALOPATHY Dr. Arun R Nair Dept. of Practice of Medicine

Portosystemic encephalopathy (PSE) v Chronic Neuropsychiatric Syndrome secondary to cirrhosis. Acute encephalopathy can occur in acute hepatic failure. v PSE can occur in portal hypertensive patients due to spontaneous ‘shunting’, or in those with surgical or TIPS/TIPSS shunts (Transjugular Intrahepatic Porto. Systemic Shunt). v Encephalopathy is potentially reversible.

Pathogenesis v The mechanism is unknown but several factors are involved. v In cirrhosis, the portal blood bypasses the liver via the collaterals and the ‘toxic’ metabolites pass directly to the brain to produce the encephalopathy. v Many ‘toxic’ substances may be causative factors, principally ammonia, but also free fatty acids, mercaptans and accumulation of false neurotransmitters (octopamine) or activation of the γaminobutyric acid (GABA) inhibitory neurotransmitter system.

v Increased blood levels of aromatic amino acids (tyrosine and phenylalanine) and reduced branched chain amino acids (valine, leucine and isoleucine) also occur. v Ammonia has a major role; ammonia-induced alteration of brain neurotransmitter balance – especially at the astrocyte neurone interface – is the leading pathophysiological mechanism. v Ammonia is produced by intestinal bacteria breaking down protein.

Clinical features v An acute onset often has a precipitating factor. v The patient becomes increasingly drowsy and comatose. v Chronically, there is a disorder of personality, mood and intellect, with a reversal of normal sleep rhythm. v These changes may fluctuate, and a history from a relative must be obtained. v The patient is irritable, confused, disorientated and has slow slurred speech.

v General features include nausea, vomiting and weakness. v Coma occurs as the encephalopathy becomes more marked, but there is always hyperreflexia and increased tone. v Convulsions are so very rare that other causes must be looked for. Signs include: Ø Fetor hepaticus (a sweet smell to the breath) Ø A coarse flapping tremor seen when the hands are outstretched and the wrists hyperextended (asterixis) Ø Constructional apraxia, with the patient being unable to write or draw, e. g. a five-pointed star.

Ø Decreased mental function, which can be assessed by using the serial-sevens test. A trail-making (or connection) test (the ability to join numbers and letters (in chronological order) with a pen within a certain time – a standard psychological test for brain dysfunction) is prolonged. Diagnosis is clinical. Routine liver biochemistry merely confirms the presence of liver disease, not the presence of encephalopathy.

Additional investigations Electroencephalography (EEG) shows a decrease in the frequency of the normal α-waves (8– 13 Hz) to α-waves of 1. 5– 3 Hz. These changes occur before coma supervenes.

Course and prognosis v Acute encephalopathy in acute liver failure has a very poor prognosis as the disease itself has a high mortality. v In cirrhosis, chronic PSE is very variable and adversely affects prognosis. v Very rarely with chronic portosystemic shunting, an organic syndrome with cerebellar signs or choreoathetosis can develop, as well as a myelopathy leading to a spastic paraparesis due to demyelination. v Patients should be referred to a liver transplant centre.

Renal failure (hepatorenal syndrome) v The hepatorenal syndrome occurs typically in a patient with advanced cirrhosis, portal hypertension with jaundice and ascites. v The urine output is low with a low urinary sodium concentration, a maintained capacity to concentrate urine (i. e. tubular function is intact) and almost normal renal histology. v The renal failure is described as ‘functional’. v It is sometimes precipitated by over vigorous diuretic therapy, NSAIDs, diarrhoea or paracentesis, and infection, particularly spontaneous bacterial peritonitis.

v The mechanism is similar to that producing ascites. v The initiating factor is thought to be extreme peripheral vasodilatation, possibly due to nitric oxide, leading to an extreme decrease in the effective blood volume and hypotension. v This activates the homeostatic mechanisms, causing a rise in plasma renin, aldosterone, noradrenaline (norepinephrine) and vasopressin, leading to vasoconstriction of the renal vasculature. v There is an increased preglomerular vascular resistance causing the blood flow to be directed away from the renal cortex.

v This leads to a reduced glomerular filtration rate and plasma renin remains high. v Salt and water retention occur with reabsorption of sodium from the renal tubules. v There is also a decrease in cardiac output inappropriate to the degree of systemic vasodilatation, which further exacerbates the haemodynamic abnormalities.

ALCOHOLIC LIVER DISEASE

v Alcoholic fatty liver disease will develop in nearly 90% of individuals who consume alcohol heavily (on average, >6 drinks per day), but only some individuals develop the more severe conditions of alcoholic hepatitis and alcoholic cirrhosis. v Genetic predisposition is likely to play a role in the pathogenesis of acute alcoholic hepatitis and alcoholic cirrhosis, but these genetic factors have not been well defined. v Although most individuals who consume alcohol do not consume it excessively and do not develop any physical or social consequences, some alcoholics consume sufficient alcohol and, presumably because of other predisposing factors, develop alcoholic liver disease.

v Nearly 50% of the patients with alcoholic hepatitis have preexisting cirrhosis, and individuals who do not yet have cirrhosis are at high risk for its development, especially if they continue to consume alcohol. PATHOBIOLOGY v The mechanisms underlying alcoholic liver injury can be broadly categorized into those caused by the effects of alcohol directly on hepatocytes and those caused by the effects mediated by Kupffer cells.

v Chronic alcohol consumption increases gut permeability, and the resulting portal endotoxemia activates Kupffer cells. v Activated Kupffer cells release a number of proinflammatory mediators. These include tumor necrosis factor-α (TNF- α); transforming growth factor-β 1; interleukins 1, 6, 8, and 10; and platelet derived growth factor. v TNF-α has plethora of biologic effects and causes hepatocyte apoptosis, whereas transforming growth factor-β 1 and platelet derived growth factor play important roles in stellate cell activation, collagen production, and hepatic fibrosis.

v Women are at higher risk; for example, the risk of alcoholic cirrhosis increases after 10 years of alcohol consumption at quantities of more than 60 to 80 g/ day in men, whereas in women, it can develop at quantities of only more than 20 g/day. v The type of alcoholic beverage consumed may not be as critical, but “spirits” and beer may be more hepatotoxic than wine. v Polymorphisms in genes associated with alcohol metabolism (alcohol and aldehyde dehydrogenases and cytochrome P-450 enzymes) and dysregulated cytokine production (e. g. , TNF-α) may also influence genetic susceptibility.

v In patients with other forms of chronic liver disease (e. g. , viral hepatitis B or C), concomitant alcohol consumption significantly aggravates liver injury. CLINICAL MANIFESTATIONS v Patients with alcoholic liver disease may have signs and symptoms from underlying alcoholism as well as those caused by liver disease. v The clinical features of liver disease will depend on the stage of alcoholic liver disease, that is, whether a patient has alcoholic fatty liver or more advanced liver disease, such as alcoholic hepatitis and cirrhosis

v chronic alcoholism include palmar erythema, spider nevi, bilateral gynecomastia(oestrogen), testicular atrophy (Hypogonadism), bilateral parotid enlargement(neuropathy with nutritional imbalance) , and Dupuytren contractures. v Patients with alcoholic fatty liver disease are generally asymptomatic, but some patients may have anorexia, fatigue, right upper quadrant discomfort, and tender hepatomegaly. v Patients with alcoholic hepatitis may have a more dramatic presentation with severe malaise, fatigue, anorexia, fever, evidence of protein-calorie malnutrition, and features of decompensated liver disease, including jaundice, coagulopathy, ascites, and encephalopathy

v Physical examination invariably shows at least some features of chronic alcoholism, and jaundice, ascites, and splenomegaly are common. v The laboratory examination findings are typically abnormal. v Common hematologic abnormalities include leukocytosis with neutrophil predominance, macrocytic anemia, thrombocytopenia, and prolonged prothrombin time. v Liver biochemistries are abnormal with an elevated AST and ratio of AST to alanine aminotransferase (ALT), alkaline phosphatase, γ-glutamyl transpeptidase, and total bilirubin but decreased levels of serum albumin.

v The AST rarely exceeds 300 IU/L. v Serum electrolyte abnormalities including hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia are frequent. v Patients with alcoholic cirrhosis have the same clinical features that are common to other types of cirrhosis but also with striking features of underlying chronic alcoholism.

DIAGNOSIS v The diagnosis of alcoholic liver disease strongly depends on the history of excessive alcohol consumption and the presence of liver disease. v Although laboratory abnormalities are not specific for alcoholic liver disease, they can be suggestive in the context of excessive alcohol consumption. v An AST/ALT ratio of more than 2 is typical in alcoholic liver disease, and ALT values greater than 150 to 200 IU/L are very rare in alcoholic liver disease.

v Hepatic imaging by ultrasound, computed tomography, or magnetic resonance imaging will show changes consistent with hepatic steatosis or more advanced forms of liver disease, such as cirrhosis and portal hypertension. v Liver biopsy is the key to precisely characterizing the nature of alcoholic liver disease and determining whether a patient has fatty liver or more advanced alcoholic hepatitis. PROGNOSIS Alcoholic fatty liver is generally reversible with total abstinence for a few months. Alcoholic hepatitis carries high mortality, with nearly 40% of patients dying within 6 months after its presentation.