Alcohol is a toxic substance to the liver and remains one of the most common causes of chronic liver disease.

The spectrum of ALD is broad and a single patient may be affected by more than one of the following conditions;fatty liver, alcoholic hepatitis or alcoholic cirrhosis.

EPIDEMIOLOGY

• ALD does not occur below a threshold of 21 units/week in women and 28 units/week in men. One unit is equal to 8g of alcohol , one glass of wine (125ml) or one 240ml can of 3.5-4% of beer. The average alcohol consumption of an individual with cirrhosis is 160g/day for an average of 8 years. Approx. 30-40 units of alcohol per week can induce cirrhosis in 3%-8% of individuals over 12 years.Fatty liver is the most commonly observed abnormality and occurs in upto 90% of alcoholics.
• Alcoholic cirrhosis is a common cause of ESLD , cirrhosis and hepatocellular carcinoma.

AETIOLOGY

• Acetaldehyde: 80% of alcohol is metabolised to acetaldehyde by enzyme alcohol dehydrogenase. Acetaldehyde forms adducts with cellular proteins in hepatocytes which activate the immune system leading to cell injury.
• 20% of alcohol is metabolised by the mixed function oxidase enzymes of the smooth endoplasmic reticulum. Cytochrome CYP2E1 is induced by alcohol, which increases oxygen consumption and lipid peroxidation. Microsomal peroxidation leads to oxygen free radicals which can induce mitochondrial damage.
• Cytokines: increased endotoxin is released into blood in alcoholic hepatitis via increased gut permeability. TNF-? production is increased from monocytes . release of IL-1,2 and 8 also occurs. These cytokines are also involved in fibrogenesis.

PATHOGENESIS

Cirrhosis develops when there is chronic and severe inflammation of the liver for an extended period of time. The regenerative capacity of the liver is enormous however over a long time fibrosis develops.

And when at least 70-80% of liver function has been lost the synthetic capacity of the liver is diminished.

PATHOLOGICAL FEATURES OF ALCOHOLIC LIVER DISEASE

• Alcoholic hepatitis: lipogranuloma
• Neutrophil infiltration
• Mallory’s hyaline
• Pericellular fibrosis
• Macrovesicular steatosis
• Fibrosis and cirrhosis
• Central hyaline sclerosis

CLINICAL FEATURES

Alcohol is a toxic substance to the liver and remains one of the most common causes of chronic liver disease.

The spectrum of ALD is broad and a single patient may be affected by more than one of the following conditions;

fatty liver, alcoholic hepatitis or alcoholic cirrhosis.

FATTY LIVER

-usually asymptomatic , hepatomegaly and mild liver enzyme abnormalities.

-fatty liver may be reversible with abstinence.

ALCOHOLIC HEPATITIS

-fever , upper abdominal pain , anorexia , nausea, vomiting, weight loss and jaundice.

-hepatomegaly and in severe cases features of portal hypertension (ascites , encephalopathy and gastrointestinal bleeding).

CIRRHOSIS

-large, normal or small liver

-ascites, varices, encephalopathy

-hepatocellular carcinoma

-stigmata of chronic liver disease:

Jaundice, spider telangiectasis, palmar erythema, cyanosis, parotid swelling, Dupuytren’s contracture, loss of libido , hair loss, gynaecomastia , testicular atrophy, impotence , breast atrophy , irregular menses, amenorrhoea , bruises, purpura , epistaxis , menorrhagia , splenomegaly, collateral vessels, variceal bleeding, hepatic encephalopathy, digital clubbing.

INVESTIGATION

1. Macrocytosis in the absence of anemia may suggest and support history of alcohol misuse.
2. In alcoholic fatty liver mild elevation in serum aminotransferases (AST higher than ALT ratio AST:ALT>2) and ALP.
3. In alcoholic hepatitis elevation in serum aminotransferases(AST higher than ALT) and ALP.
4. Hyperbilirubinemia, prolongation of PT ,lactic acidosis, hyperuricemia , elevated TGL , thrombocytopenia ketoacidosis, hypoglycaemia , cdt>20u/l , raised GGT.
5. Laboratory abnormalities with poor prognosis include renal failure, leukocytosis, a markedly elevated total bilirubin and prolongation of PT that do not normalise with vitamin K.
6. A Discriminant function(DF) or Maddrey’s score enables to assess prognosis in alcoholic hepatitis.
7. DF=4.6-[PT patient - PT control]+serum bilirubin(mg/dl)
8. A value over 32 implies severe liver disease with a poor prognosis.

TREATMENT

Behavioural  cessation of alcohol is the single most important treatment. Abstinence is even effective.

Good Nutrition is very important and enteral feeding via a fine-bore nasogastric tube may be needed in severely ill patients.

-Patients with DF>32 and hepatic encephalopathy may benefit from steroid therapy. Oral prednisone can be started at 40-60mg/day and subsequently tapered.

Pentoxifylline 400mg PO tid is a nonselective phosphodiesterase inhibitor with anti-inflammatory properties ; reduce incidence of hepatorenal failure and has shown improved survival in severe alcoholic hepatitis.

S-adenosylmethionine, antioxidants , tumor necrosis factor inhibitors are under investigation in ALD.

Dr Mahesh Shrestha

Fulminant hepatic failure (FHF) which is defined as the severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of preexisting liver disease ( encephalopathy within 8 weeks of the onset of symptoms in a previously healthy liver).

Defined originally further as-

• occurring withion 8 weeks of onset of precipitating illness.
• In the absence of evidence of pre-existing liver disease

Classified as-

1. Hyperacute – occurring in less than 7 days. Cerebral edema is common. Commonly caused by viral hepatitis and paracetamol poisoning .
2. Acute- Occuring between 1 week to 4 weeks. Cerebral edema is common.  Follows Drug toxicity and cryptogenic causes.
3. Sub-acute- Occuring between 4 weeks to 12 weeks. Cerebral edema is uncommon. Cryptogenic causes and drugs are main causes.

Causes of acute liver failure

Clinical Assessment-

• Mild episodic symptoms may progress up to hepatic encephalopathy later causing severe cerebral disturbances.
• Reduced alertness, poor concentration
• Behavioural changes- aggressive and restless.
• Altered sensorium
• Flapping tremor or Asterexis
• Fetor hepaticus ( typical smell breath in liver disease)
• Abnormal pupilary reaction
• Hypertension, Bradycardia, hyperventilation
• Profuse sweating, Myoclonus, focal fits, decerebrate posturing and late- Papilloedema

General Symptoms are-

Weakness, nausea and vomiting, right hypochondrial discomfort

Examination may reveal-Jaundice, Reye’s Syndrome

• Fetor hepaticus
• Hepatomegaly is unusual
• Sudden onset ascites
• Normal spleen size

Investigation useful for assessing the problem are-

1. Toxicology Screen of blood and urine for drugs and toxins
2. Hepatitis Virus Antibody screening and test to detect CMV, EBV, HSV etc
3. Liver function test
4. Serum Caeruloplasmin level,  Serum copper, Urinary copper, Slit lamp eye examination to rule out Wilson’s Disease
5. Auto-antibodies like ANF, ASMA, LKM
6. Utrasonography – Liver and Doppler of Hepatic veins

Management-

1. Patient is critical and need ICU care
2. Monitor – Neurological, Cardiorespiratory functions
3. Fluid balance- maintainance and input/output charting
4. Blood Analysis- Arterial Blood Gas Analysis, Peripheral blood count, Electrolytes,Glucose-2 hourly
5. Kidney function test
6. Prothrombin time
7. Infection Survillence-
8. Culture Blood, urie throat, sputum, cannula sites
9. Chest x-ray

Treatment-

1. Conservative treatrment is Dialysis for removal of toxins and drugs
2. Paracetamol Poisoning-NAC (Read Paracetamol poisoning in children)
3. Liver transplant

Monitor the adverse prognostic criteria.

Complications – ( HERMIM – Mnemonic)

• Hypoglycemia
• Encephalopathy and cerebral edema
• Renal failure
• Metabolic acidosis
• Infection
• MODS

Survival – 1 yr =60%

Anatomy of liver

The liver derives blood from the hepatic artery (20%)  and the portal vein (80%).

The hepatic artery usually arises from the aorta at the coeliac axis and divides into the right and left branches at the hilus.
— —The venous drainage from the liver is by three large hepatic veins  right, middle and left  into the inferior vena cava (IVC), just below the diaphragm.

—The 3 major forms of liver abscess,

classified by etiology, are as follows: — —

1. Pyogenic abscess, which is most often polymicrobial, accounts for 80% of hepatic abscess cases in the United States. —
2. Amebic abscess due to Entamoeba histolytica accounts for 10% of cases. —
3. Fungal abscess, most often due to Candida species, accounts for less than 10% of cases.
—

Risk factors : DM, underlying hepatobiliary or pancreatic malignancy, and liver transplant. Geographic factors may also play a role. —mortality rate : 2 ~ 12% (mortality appears to be related to underlying comorbidities rather than to the abscess itself.)

Pathophysiology:—

The liver receives blood from both systemic and portal circulations. Increased susceptibility to infections would be expected given the increased exposure to bacteria. —However, Kupffer cells lining the hepatic sinusoids clear bacteria so efficiently that infection rarely occurs.  Multiple processes have been associated with the development of hepatic abscesses

Causes:

—Infection through portal vein:

acute appendicitis, diverticulitis, amoebic colitis, UC

—Infection through the CBD:

stricture, periampullary Ca, rec. cholangitis, ERCP

—Infection through hepatic artery:

septicemia, pyaemia

—Extension abscess:

sudiaphragmatic abscess, empyema thoracis, injuries

—Infection through umbilicus:

neonatal umbilical sepsis giving rise to pyaemia

—Pyogenic liver abscess has been reported as a secondary infection of

• 1.amebic abscess
• 2.hydatid cystic cavities and metastatic and primary hepatic tumors.
• 3.complication of liver transplantation
• 4.hepatic artery embolization in the treatment of hepatocellular carcinoma
• 5.ingestion of foreign bodies, which penetrate the liver parenchyma.

• —Appendicitis was traditionally the major cause of liver abscess. —Biliary tract disease is now the most common source of pyogenic liver abscess.
• —Abscesses usually are multiple, unless they are associated with surgical interventions or indwelling biliary stents. In these instances, solitary lesions can be seen. —
• —The right hepatic lobe is affected more often than the left hepatic lobe by a factor of 2:1. Bilateral involvement is seen in 5% of cases. —The predilection for the right hepatic lobe can be attributed to anatomic considerations. The right hepatic lobe receives blood from both the superior mesenteric and portal veins, whereas the left hepatic lobe receives inferior mesenteric and splenic drainage. It also contains a denser network of biliary canaliculi and, overall, accounts for more hepatic mass. Studies have suggested that a streaming effect in the portal circulation is causative.

Symptoms:

—The most frequent symptoms of hepatic abscess include the following:

1. Fever (either continuous or spiking)
2. Chills
3. Right upper quadrant pain
4. Anorexia
5. Malaise —

• Cough or hiccoughs due to diaphragmatic irritation may be reported.
• —Referred pain to the right shoulder may be present. —
• —Individuals with solitary lesions usually have a more insidious course with weight loss and anemia of chronic disease. With such symptoms, malignancy often is the initial consideration.
• —Fever of unknown origin (FUO) frequently can be an initial diagnosis in indolent cases. —
• Afebrile presentations have been documented.

Physical Signs:

• —Fever and tender hepatomegaly -the most common signs. —
• A palpable mass need not be present.
• —Mid epigastric tenderness, with or without a palpable mass, is suggestive of left hepatic lobe involvement. —
• Decreased breath sounds in the right basilar lung zones, with signs of atelectasis and effusion on examination or radiologically, may be present. —
• A pleural or hepatic friction rub can be associated with diaphragmatic irritation or inflammation of Glisson capsule. —
• Jaundice may be present in as many as 25% of cases and usually is associated with biliary tract disease or the presence of multiple abscesses

Differential Diagnosis of Hepatic Abscess:

1.Biliary Disease 2. Hydatid Cysts 3.Cholecystitis 4. Pneumonia, Bacterial 5.Empyema, Pleuropulmonary 6.Gastritis, Acute 7.Hepatocellular Carcinoma

Lab Investigations:—

• CBC count with differential ¡Anemia of chronic disease
• Neutrophilic leukocytosis —Liver function studies
• Hypoalbuminemia and elevation of alkaline phosphatase (most common abnormalities)
• Elevations of transaminase and bilirubin levels (variable) —Blood cultures are positive in roughly 50% of cases.
• —Culture of abscess fluid should be the goal in establishing microbiologic diagnosis. ELISA for E. histolytica
• —CT and ultrasound – modalities of choice —Abscesses must be distinguished from tumors and cysts. —CT or ultrasound-guided aspiration should be sent for gram stain and culture. —Blood cultures should always be performed when liver abscess is suspected; they are positive in up to 50 percent of cases

Complications:—

Sepsis —Empyema resulting from contiguous spread or intrapleural rupture of abscess —Rupture of abscess with resulting peritonitis —Endophthalmitis when an abscess is associated with K pneumoniae bacteremia

MANAGEMENT of LIVER ABSCESS:

—Percutaneous needle aspiration Under CT scan or ultrasound guidance, needle aspiration of cavity material can be performed. Diagnostic + therapeutic.

Percutaneous drainage has become the standard of care and should be the first intervention considered for small cysts. Seldinger or trochar technique.

—For single abscesses with diameter ≤5 cm : percutaneous catheter drainage or needle aspiration is acceptable. —For single abscesses with diameter >5 cm :percutaneous management : catheter drainage is preferred over needle aspiration. ¡surgical intervention is preferred over percutaneous drainage

Medical Therapy—

• Empiric broad-spectrum antibiotics should be administered pending abscess gram stain and culture results. —
• A third generation cephalosporin such as ceftriaxone PLUS metronidazole.(Flumarin)
• —fluoroquinolone (eg, ciprofloxacin PLUS metronidazole —
• Monotherapy with a carbapenem

—follow imaging, WBC count and serum CRP —If good response – 2~4 weeks of therapy, —no or incomplete drainage- 4~6 weeks of therapy. — —Drainage catheters should remain in place until drainage is minimal (usually up to seven days).

—Open surgery can be performed by 2 approaches.

Abscess cavity was later packed with betadine gauge

• A transperitoneal approach allows for abscess drainage and abdominal exploration to identify previously undetected abscesses and the location of an etiologic source.
• For high posterior lesions, a posterior transpleural approach can be used.
• —A laparoscopic approach is also commonly used in select cases.

( Source Medscape-emedicine, Manipal, Bailey and Love and various sites).

1. Cirrhotic patients with ascites at admission
2. Cirrhotic patients with ascites and signs or symptoms of infection: fever, leukocytosis, abdominal pain
3. Cirrhotic patients with ascites who present with a clinical condition that is deteriorating during hospitalization: renal function impairment, hepatic encephalopathy, gastrointestinal bleeding
4. Patients with new-onset ascites

Peritoneal Fluid Analysis:

Additional Analyses of Ascitic Fluid

Differential Diagnosis of Ascites According to the Serum Ascites Albumin Gradient

The diagnosis of SBP is suggested by a polymorphonuclear (PMN) cell count in excess of 250 cells per cubic millimeter in the absence of evidence of an alternative source of infection (secondary peritonitis), such as viscus perforation or intraabdominal abscess.

Determination of total protein, lactate dehydrogenase, and glucose levels in ascitic fluid may aid in the differentiation between SBP and secondary peritonitis. Culture is used to confirm the diagnosis of SBP.

Ascitic fluid infections

Types

1. Spontaneous bacterial peritonitis (SBP). Most common infection in patients with ascites and cirrihosis. Ascitic fluid infection with positive bacterial culture, neutrophil count ?250/ml and no surgically treatable source of infection. Bacterial cultures almost invariably yield a single growth. The presence of >1 organism suggests secondary peritionitis.
2. Culture negative neutrocytic ascites. Diagnostic criteria as for SBP but cultures are negative. Other causes of raised ascitic fluid neutrophil count need to be excluded (eg peritoneal carcinomatosis, pancreatitis, TB peritonitis). Clinical, prognostic and therapeutic characteristics are similar to those of SBP and this condition should be treated in a similar fashion to SBP.
3. Mononmicrobial non-neutrocytic bacterascites. Positive culture but neutrophils <250/ml. Clinical course is dependent on the presence/absence of clinical features. Those with clinical features of ascitic fluid infection have similar morbidity/mortality to those with SBP.
4. Secondary bacterial peritonitis. Positive cultures (usually polymicrobial), neutrophils 250/ml, and surgically treatable source of infection. Clinical features do not distinguish SBP from secondary bacterial peritonitis. Ascites usually meets 2 of the following: total protein >1g/dL, glucose <50 mg/dL, LDH >225 U/ml (or higher than the upper limit of normal for serum)
5. * Polymicrobial bacterascites. Gram stain or culture reveals multiple organisms but neutrophils <250/ml. Usually due to inadvertent puncture of intestine during paracentesis (risk: 1/1000). If ascitic fluid protein >1g/dL colonization usually resolves spontaneously

Aetiology & Pathogenesis

- seemingly innocuous procedures can lead to transient bacteraemia and SBP in cirrhotics (eg NG tube placement, endoscopy, IV catheter insertion, bladder catheterization)
- usually develops when the volume of ascites is sizeable but can occur even when fluid is difficult to detect on physical examination
- E.coli, Strep (usually pneumococcus) and Klebsiella account for 3/4 of cases. Gram negative infection more common than gram positive. Anaerobes rarely isolated
- current view is that SBP is the result of bacterial overgrowth in the small intestine followed by bacterial translocation across the intestinal wall. Because of impaired immune response in cirrhotics and portosystemic shunts the bacteria then spread into the systemic circulation and seed in ascites.
Predisposing factors

* Severity of liver disease:
70% of cases occur in patients with Child’s grade C with most of the rest occuring in patients with Child’s grade B.
Total ascites protein <1 g/dL predisposes to SBP because it correlates with complement levels and opsonic activity
* GI bleeding
20% of patients with cirrhosis and ascites presenting with a GI bleed have SBP
* Bacteriuria
* Previous SBP
Recurrence rates: 43% by 6 months, 69% by 1 year and 74% by 2 years

Clinical features

1. signs may be absent in up to 1/3
2. fever/hypothermia
3. abdominal pain and tenderness
4. rigidity is not a feature in patients with infected ascites, even if there is a free perforation of the intestine. This is a result of the large volume of ascites preventing contact between the visceral and parietal peritoneal surfaces
5. hepatic encephalopathy
6. diarrhoea
7. ileus
8. shock
9. important to have high index of suspicion and low threshold for diagnostic paracentesis. Unexplained deterioration in a patient with cirrhosis and ascites should lead to diagnostic paracentesis

Investigations

• diagnostic tap of ascites. Innoculate some fluid directly into blood culture bottle as well as sending fluid for gram stain (often not helpful) and cell and differential count. Suspect SBP if neutrophil count > 250/ml. Other tests which may be helpful include total protein, glucose (in malignancy or gut perforation), LDH ( in spontaneous bacterial peritonitis) , amylase ( in pancreatitis). Risk of paracentesis is small despite almost invariable impairment of clotting in these patients. Approx. 1% risk of significant abdominal wall haematoma, 0.01% risk of haemoperitoneum and 0.01% risk of iatrogenic infection
• follow up paracentesis probably not necessary if response to treatment is dramatic, setting is typical and infection is monomicrobial. However if there are features to suggest secondary peritonitis paracentesis should be repeated (usually after 48 h)
• peritonitis secondary to abscess or perforated viscus should be suspected if WCC >10,000/ml, ascitic protein is elevated, cultures of fluid grow anaerobes or multiple organisms, or follow-up paracentesis after 48 h of treatment reveals persistently positive cultures or a rising WCC

Treatment

1. Spontaneous bacterial peritonitis, culture negative neutrocytic ascites, symptomatic monomicrobial bacterascites
2. 3rd generation cephalosporin (cefotaxime 2g 8 hrly) until sensitivity known. 5 day course satisfactory even for patients who are bacteraemic.
3. Asymptomatic monomicrobial bacterascites
4. Repeat paracentesis after 48 h.
5. Treat with cefotaxime if symptoms develop or neutrophil count in repeat sample ?250/ml

References:

1. Fernandez J, Bauer TM, Navasa M, Rodes J. Diagnosis, treatment and prevention of spontaneous bacterial peritonitis. Baillieres Best Pract Res Clin Gastroenterol. 2000 Dec;14(6):975-990.
2. Thomsen TW, Shaffer RW, White B, Setnik GS. Videos in clinical medicine. Paracentesis. N Engl J Med. 2006 Nov 9;355(19):e21.