1. Internal Medicine & Pediatrics December 9, 2004
Liver Cirrhosis
K. Dionne Posey, MD, MPH
Internal Medicine & Pediatrics December 9, 2004

2. Introduction
The two most common causes in the United States are alcoholic liver disease and hepatitis C, which together account for almost one-half of those undergoing transplantation

3. Introduction 12th leading cause of death in the united states in 2002
On average about 27,000 deaths per year
Patients with cirrhosis are susceptible to a variety of complications and their life expectancy is markedly reduced

4. Exactly How Much Do You Drink?
Estimated that the development of cirrhosis requires, on average, the ingestion of 80 grams of ethanol daily for 10 to 20 years
This corresponds to approximately one liter of wine, eight standard sized beers, or one half pint of hard liquor each day

5. Pathophysiology Irreversible chronic injury of the hepatic parenchyma
Extensive fibrosis - distortion of the hepatic architecture
Formation of regenerative nodules

6. Clinical Manifestations
Spider angiomas
Palmar erythema
Nail changes
Muehrcke's nails
Terry’s nails
Gynecomastia
Testicular atrophy

7. Clinical Manifestations
Muehrcke's nails
Terry’s nails
Muehrcke's nails
are paired horizontal white bands separated by normal color.
The exact pathogenesis is unknown but it is
believed to be caused by hypoalbuminemia
They are not specific for cirrhosis since they may also be seen in other conditions associated with a low serum albumin, such as the nephrotic syndrome.
Terry's nails.
first reported this nail finding in 1954 in association with patients who had hepatic cirrhosis.
His initial description detailed the nail bed as white in appearance with a ground-glass opacity.
In addition, the nail bed contained a pink distal band that measured 1 to 2 mm in width.
In 1984, Holzberg and colleagues revised the original inclusion criteria for classifying a patient as having Terry's nails to what is used today. The affected nails have a nail bed that is white or light pink with a distal transverse band measuring 0.5 to 3.0 mm in width that is pink to brown in color. The lunula of the nail may or may not be present. The degree of pallor of the nail bed and the darkness of the distal band can vary based on how long the underlying systemic disease has affected the patient.
Terry's nails are associated with several diseases and advancing age. Type 2 diabetes mellitus, congestive heart failure, chronic renal failure, and cirrhosis are all systemic diseases that are associated with Terry's nails. The pathogenesis of these nail changes is unclear, but it is believed to involve changes in the microvascular system.
aging is a common cause of Terry's nails

8. Clinical Manifestations
Fetor hepaticus
Jaundice
Asterixis
Pigment gallstones
Parotid gland enlargement
Cruveilhier-Baumgarten murmur
Hepatomegaly
Splenomegaly
Caput medusa

11. Laboratory Studies
most common measured laboratory test classified as LFTs include
the enzyme tests (principally the serum aminotransferases, alkaline phosphatase, and gamma glutamyl transpeptidase), the serum bilirubin
tests of synthetic function (principally the serum albumin concentration and prothrombin time)

12. Radiologic Modalities
Can occasionally suggest the presence of cirrhosis, they are not adequately sensitive or specific for use as a primary diagnostic modality
Major utility of radiography in the evaluation of the cirrhotic patient is in its ability to detect complications of cirrhosis

13. Diagnosis Liver biopsy
Obtained by either a percutaneous, transjugular, laparoscopic, or radiographically-guided fine-needle approach
Sensitivity of a liver biopsy for cirrhosis is in the range of 80 to 100 percent depending upon the method used, and the size and number of specimens obtained
The gold standard for diagnosis of cirrhosis is examination of an explanted liver at autopsy or following liver transplantation during which the architecture of the entire liver can be appreciated.
However, liver biopsy is not necessary if the clinical, laboratory, and radiologic data strongly suggest the presence of cirrhosis.

14. Diagnosis
not necessary if the clinical, laboratory, and radiologic data strongly suggest the presence of cirrhosis
liver biopsy can reveal the underlying cause of cirrhosis

15. Histopathology
Alcoholic Cirrhosis Alcohol coming from the gut first makes contact with the hepatocytes nearest the portal triad. These liver cells, therefore, will be affected first by the toxicity of alcohol. The fibrosis (in blue in this trichrome stain) is coming "from the outside in" with respect to the lobule. At this stage, the lobules themselves are spared.

16. Histopathology
Hepatitis

17. Histopathology
Hemochromatosis

18. Histopathology
Nonalcoholic steatohepatitis

20. Morphologic Classification
Micronodular cirrhosis
Nodules less than 3 mm in diameter
Believed to be caused by alcohol, hemochromatosis, cholestatic causes of cirrhosis, and hepatic venous outflow obstruction

21. Morphologic Classification
Macronodular cirrhosis
Nodules larger than 3 mm
Believed to be secondary to chronic viral hepatitis

22. Morphologic Classification
Relatively nonspecific with regard to etiology
The morphologic appearance of the liver may change as the liver disease progresses
micronodular cirrhosis usually progresses to macronodular cirrhosis
Serological markers available today are more specific than morphological appearance of the liver for determining the etiology of cirrhosis
Accurate assessment of liver morphology may only be achieved at surgery, laparoscopy, or autopsy

23. Evaluation of Cirrhosis
Evaluation of the patient with cirrhosis
a specific etiology can usually be determined by the history combined with serologic and histologic evaluation. The two most common causes in the United States are alcoholic liver disease and hepatitis C

24. Complications Ascites Spontaneous Bacterial Peritonitis
Hepatorenal syndrome
Variceal hemorrhage
Hepatopulmonary syndrome
Once a patient develops complications of cirrhosis, they are considered to have decompensated disease. The high morbidity and mortality of cirrhosis is secondary to these devastating complications. The quality of life and survival of cirrhotic patients can be improved by the prevention and treatment of these complications

25. Complications Other Pulmonary syndromes Hepatic Encephalopathy
Hepatic hydrothorax
Portopulmonary HTN
Hepatic Encephalopathy
Hepatocellular carcinoma

26. Ascites Accumulation of fluid within the peritoneal cavity
Most common complication of cirrhosis
Two-year survival of patients with ascites is approximately 50 percent
Nearly 60 percent of all patients with compensated cirrhosis will develop ascites in 10 years
The two-year survival of patients with ascites is approximately 50 percent
85 percent of all cases of ascites in the US are due to liver cirrhosis
ascites is the most common complication of cirrhosis

27. Ascites Assessment of ascites Grading Older system -subjective
Grade 1 — mild; Detectable only by US
Grade 2 — moderate; Moderate symmetrical distension of the abdomen
Grade 3 — large or gross asites with marked abdominal distension
Older system -subjective
1+ minimal, barely detectable
2+ moderate
3+ massive, not tense
4+massive and tense
Grading — A grading system for ascites has been proposed by the International Ascites Club :
    Grade 1 — mild ascites detectable only by ultrasound examination     Grade 2 — moderate ascites manifested by moderate symmetrical distension of the abdomen     Grade 3 — large or gross asites with marked abdominal distension.
An older system that grades ascites from 1+ to 4+ is also used. In this system 1+ is minimal and barely detectable, 2+ is moderate, 3+ is massive but not tense, and 4+ is massive and tense

28. Ascites Imaging studies for confirmation of ascites
Ultrasound is probably the most cost-effective modality
Patients with ascites should be "imaged" to confirm or refute the presence of ascites, cirrhosis, or malignancy.
Ultrasound is probably the most cost-effective modality. Another advantage of ultrasound is that it involves no radiation or intravenous access, and no risk of contrast allergy or nephropathy. These features contrast dramatically with computerized tomographic scanning, although ascites can be seen easily on CT

29. Ascites

30. Who gets a belly tap?

31. What do I want to order ?
Serum-to-ascites albumin gradient — The serum-to-ascites albumin gradient (SAAG) accurately identifies the presence of portal hypertension and is more useful than the protein-based exudate/transudate concept.
The SAAG is easily calculated by subtracting the ascitic fluid albumin value from the serum albumin value, which is obtained on the same day.
    The presence of a gradient 1.1 g/dL (11 g/L) indicates that the patient has portal hypertension with 97 percent accuracy.     A gradient <1.1 g/dL (<11 g/L) indicates that the patient does not have portal hypertension [25]. The SAAG need not be repeated after the initial measurement.

32. Ascites
Treatment aimed at the underlying cause of the hepatic disease and at the ascitic fluid itself
Dietary sodium restriction
Limiting sodium intake to 88 meq (2000 mg) per day
treatment of cirrhotic ascites is aimed at the underlying cause of the hepatic disease and at the ascitic fluid itself.
Threshold for initiating treatment — Once a patient with cirrhosis develops clinically apparent ascites, it is unlikely to disappear without specific treatment. A possible exception to this rule is the alcoholic who has a huge dietary sodium intake and a large reversible component of liver disease; ascites may resolve in such patients following cessation of drinking and reduction of sodium intake
Limiting sodium intake to 88 meq (2000 mg) per day
Successful treatment of the patient with ascites depends upon an accurate diagnosis regarding the cause of ascites formation
Success is defined as minimization of ascitic fluid volume and peripheral edema without intravascular volume depletion

33. Ascites
The most successful therapeutic regimen is the combination of single morning oral doses of Spironolactone and Furosemide, beginning with 100 mg and 40 mg
Two major concerns with diuretic therapy for cirrhotic ascites:
Overly rapid removal of fluid
Progressive electrolyte imbalance

34. Spontaneous Bacterial Peritonitis
Infection of ascitic fluid
Almost always seen in the setting of end-stage liver disease
The diagnosis is established by
A positive ascitic fluid bacterial culture
Elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN) count ( >250 cells/mm3)
is an infection of preexisting ascitic fluid without evidence for an intraabdominal secondary source such as a perforated viscus
Manifestations of SBP include
Fever - Fever is clearly the most common manifestation of SBP. It is important to appreciate in this regard that patients with advanced cirrhosis are usually mildly hypothermic If this opportunity is missed, shock ensues, followed rapidly by multisystem organ failure.
abdominal pain -the pain can be very subtle in SBP due to the presence of ascites. The pain is usually diffuse and continuous; it is different from the pain induced by stretching of the abdominal wall due to tense ascites
abdominal tenderness
altered mental status -The Reitan trail test is helpful in detecting subtle changes in mental status in the patient with cirrhosis [7]. This is a connect-the-number test that is timed. A time greater than 60 seconds is pathologic in all age groups.
Some patients are asymptomatic and present with only mild laboratory abnormalities
The index of suspicion for SBP must be high with a low threshold for diagnostic paracentesis.
Without early treatment, mortality is high. Efforts to prevent SBP should be made in high-risk patients.
Paralytic Ileus, hypotension, hypothermia — These more severe signs are indicative of advanced infection and a poor likelihood of survival.
These include leukocytosis, metabolic acidosis, and azotemia.

35. Spontaneous Bacterial Peritonitis
Clinical manifestations:
Fever
Abdominal pain
Abdominal tenderness
Altered mental status
Measurement of total protein, glucose, and lactate dehydrogenase (LDH) in ascites may also be of value in distinguishing SBP from gut perforation into ascites
Patients with ascitic fluid that has a neutrophil count 250 cells/mm3 and meets two out of the following three criteria are unlikely to have SBP and warrant immediate evaluation to determine if gut perforation into ascites has occurred:
    Total protein >1 g/dL     Glucose <50 mg/dL (2.8 mmol/L)     LDH greater than the upper limit of normal for serum

36. Hepatorenal syndrome
acute renal failure coupled with advanced hepatic disease (due to cirrhosis or less often metastatic tumor or severe alcoholic hepatitis)
characterized by:
Oliguria
benign urine sediment
very low rate of sodium excretion
progressive rise in the plasma creatinine concentration
The hepatorenal syndrome
Rather than being a new disease, the hepatorenal syndrome usually represents the end-stage of a sequence of reductions in renal perfusion induced by increasingly severe hepatic injury.
The initial reductions in glomerular filtration rate are often masked clinically since associated decreases in muscle mass and hepatic urea production minimize elevations in the plasma creatinine concentration and blood urea nitrogen.
The diagnosis is one of exclusion, being made when other causes of renal dysfunction have been excluded.
In particular, volume depletion (as with overly-rapid diuresis) can mimic all of the findings of hepatorenal syndrome. The prognosis is poor unless hepatic function improves

37. Hepatorenal Syndrome Reduction in GFR often clinically masked
Prognosis is poor unless hepatic function improves
Nephrotoxic agents and overdiuresis can precipitate HRS
Initial reductions in glomerular filtration rate are often clinically masked since associated decreases in muscle mass and hepatic urea production minimize elevations in the plasma creatinine concentration and blood urea nitrogen

38. Variceal hemorrhage
Occurs in 25 to 40 percent of patients with cirrhosis
Prophylactic measures
Screening EGD recommended for all cirrhotic patients
Variceal hemorrhage is a devastating complication
Prior to the widespread use of current therapies for acute variceal hemorrhage, the mortality rate of a single variceal hemorrhage was 30 percent and only one-third of patients survived for one year
Although survival has improved with modern techniques for controlling variceal hemorrhage, mortality rates remain high
We recommend screening all cirrhotic patients for gastroesophageal varices with upper gastrointestinal endoscopy.
Patients with varices should be treated with prophylactic measures. This most commonly involves treatment with a nonselective beta blocker, which reduces the risk of variceal bleeding.

39. Hepatopulmonary syndrome
Liver disease
Increased alveolar-arterial gradient while breathing room air
Evidence for intrapulmonary vascular abnormalities, referred to as intrapulmonary vascular dilatations (IPVDs)
prevalence of HPS among patients with chronic liver disease range from 5 to 50 percent
    The hepatopulmonary syndrome (HPS) is considered to be present in patients with the following triad:
   Liver disease    Increased alveolar-arterial gradient while breathing room air    Evidence for intrapulmonary vascular abnormalities, referred to as intrapulmonary vascular dilatations (IPVDs)
Even in cirrhotic patients lacking HPS, mild hypoxemia is common and is presumably caused by ascites, with resulting diaphragmatic elevation and ventilation/perfusion mismatch.

40. Hepatic Hydrothorax
Pleural effusion in a patient with cirrhosis and no evidence of underlying cardiopulmonary disease
Movement of ascitic fluid into the pleural space through defects in the diaphragm, and is usually right-sided
Diagnosis -pleural fluid analysis
reveals a transudative fluid
serum to fluid albumin gradient greater than 1.1
Although there are reports of hepatic hydrothorax occurring in the absence of ascites, this finding is rare.

41. Hepatic hydrothorax Confirmatory study: Treatment options:
Scintigraphic studies demonstrate tracer in the chest cavity after injection into the peritoneal cavity
Treatment options:
diuretic therapy
periodic thoracentesis
TIPS

42. Portopulmonary HTN
Refers to the presence of pulmonary hypertension in the coexistent portal hypertension
Prevalence in cirrhotic patients is approximately 2 percent
Diagnosis:
Suggested by echocardiography
Confirmed by right heart catheterization
Portopulmonary hypertension.
Neither the prevalence nor the severity of portopulmonary hypertension appears to correlate with the degree of portal hypertension.
Patients with portopulmonary hypertension may present with fatigue, dyspnea, peripheral edema, chest pain, and syncope
. Patients with moderate to severe portopulmonary hypertension are difficult to treat with medical therapy and the perioperative mortality with liver transplantation is high.

43. Hepatic Encephalopathy
Spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction
Diurnal sleep pattern pertubation
Asterixis
Hyperactive deep tendon reflexes
Transient decerebrate posturing
Hepatic encephalopathy describes the spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction.
Disturbance in the diurnal sleep pattern (insomnia and hypersomnia) is a common early feature that typically precedes overt neurologic signs
More advanced neurologic features include the presence of asterixis, hyperactive deep tendon reflexes, and less commonly, transient decerebrate posturing.

44. Hepatic Encephalopathy

45. Hepatic Encephalopathy
Monitoring for events likely to precipitate HE [i.E.- variceal bleeding, infection (such as SBP), the administration of sedatives, hypokalemia, and hyponatremia]
Reduction of ammoniagenic substrates
Lactulose / lactitol
Dietary restriction of protein
Zinc and melatonin
Patients with cirrhosis should be evaluated regularly for hepatic encephalopathy, the earliest features of which can be subtle

46. Hepatocellular Carcinoma
Patients with cirrhosis have a markedly increased risk of developing hepatocellular carcinoma
Incidence in well compensated cirrhosis is approximately 3 percent per year
Patients with cirrhosis have a markedly increased risk of developing hepatocellular carcinoma (HCC).
The incidence in well compensated cirrhosis is approximately 3 percent per year
Patients with most forms of chronic hepatitis are not at an increased risk until cirrhosis develops
Exceptions to this rule are patients with chronic hepatitis B virus infection who can develop HCC in the absence of cirrhosis
Certain causes of cirrhosis appear to have a relatively increased risk for HCC. Patients with cirrhosis from hepatitis B, hepatitis C, and hemochromatosis are at the highest risk, while those with cirrhosis from autoimmune hepatitis, nonalcoholic steatohepatitis, and Wilson's disease appear to have a lower risk.
Because of the large functional reserve of the liver, patients with HCC are often asymptomatic early in its course. Thus, the diagnosis is often delayed.
Decompensation in a patient with previously compensated cirrhosis should raise the clinical suspicion that HCC has developed. Other common signs and symptoms of hepatocellular carcinoma are usually related to mass effect from the tumor and include pain, early satiety, obstructive jaundice, and a palpable mass. Hepatocellular carcinomas can rupture, causing hemoperitoneum.
Paraneoplastic manifestations include erythrocytosis, hypercalcemia, hypoglycemia, and diarrhea
The diagnosis of HCC can be suggested by marked elevations of serum alpha-fetoprotein (AFP) or by characteristic radiographic findings.
Elevated AFP is not specific for HCC since it can also be seen in patients with acute or chronic hepatitis, gonadal tumors, and pregnancy. However, rising serum AFP levels in patients with cirrhosis should raise clinical suspicion for HCC.
Levels of serum AFP greater than 500 micrograms/L in a patient with cirrhosis are virtually diagnostic
a normal AFP does not preclude a diagnosis

47. Hepatocellular Carcinoma
Symptoms are largely due to mass effect from the tumor
Pain, early satiety, obstructive jaundice, and a palpable mass
Serum AFP greater than 500 micrograms/l in a patient with cirrhosis are virtually diagnostic
Median survival following diagnosis is approximately 6 to 20 months
Treatment options for HCC are divided into
surgical therapies (ie, resection, cryoablation, and orthotopic liver transplantation),
nonsurgical therapies (ie, percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization, chemotherapy, and radiation).
Median survival following diagnosis is approximately 6 to 20 months

48. Prognostic Tools MELD (model for end-stage liver disease)
Identify patients whose predicted survival post-procedure would be three months or less
MELD = 3.8[serum bilirubin (mg/dL)] [INR] + 9.6[serum creatinine (mg/dL)] + 6.4
MELD is a prospectively developed and validated chronic liver disease severity scoring system that uses a patient's laboratory values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival.
In patients with chronic liver disease, an increasing MELD score is associated with increasing severity of hepatic dysfunction and risk of death
new allocation system has been successful in de-emphasizing waiting time as a major factor in prioritizing patients for liver transplantation. In addition, adoption of the MELD scoring system appears to have been associated with increased transplantation rates without concomitant increased mortality rates.
One such model (the Model for End Stage Liver Disease [MELD]) is based upon bilirubin levels, creatinine, INR, and the etiology of cirrhosis The MELD score has been adopted for use in allocating priorities in patients awaiting liver transplantation. The MELD score accurately predicts three-month mortality among patients on the liver transplant waiting list

49. Prognostic Tools Child-Turcotte-Pugh (CTP) score
initially designed to stratify the risk of portacaval shunt surgery in cirrhotic patients
based upon five parameters: serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy
good predictor of outcome in patients with complications of portal hypertension
It was initially developed by Child and Turcotte in 1964 to risk stratify patients undergoing shunt surgery for portal decompression The original Child-Turcotte classification system was empirically derived and incorporated serum albumin, serum bilirubin, "nutritional status", ascites, and encephalopathy.
The current CTP scoring system is based upon five parameters: serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy. The sum of the points for each of these five parameters gives the total score. Patients with chronic liver disease are placed in one of three classes (A, B, or C)
a good predictor of outcome in patients with complications of portal hypertension
based upon subjective parameters such as the degree of ascites and encephalopathy
may be altered substantially by medical intervention

50. The Child-Turcotte classification incorporates five variables that were initially designed to stratify the risk of portacaval shunt surgery in cirrhotic patients.
The variables included the serum albumin and bilirubin, ascites, encephalopathy, and nutritional status
Modified versions of these criteria, such as the Child-Pugh classification have been used to assess the risk of non-shunt operations
The Child-Pugh classification system correlates with survival; one-year survival rates for patients with Child's A, B, and C cirrhosis are approximately 100, 80, and 45 percent, respectively
Child-Pugh class can also predict the development of complications of cirrhosis.
As an example, patients with Child-Pugh class C cirrhosis are much more likely to develop variceal hemorrhage than those with Child-Pugh class A cirrhosis

51. Prognostic Tools
APACHE III (acute physiology and chronic health evaluation system)
Designed to predict an individual's risk of dying in the hospital
APACHE III scoring, the patient's age and chronic health history are worth up to 47 points. Within 24 hours of ICU admission, 17 physiologic variables are measured and may add up to a maximum of an additional 252 points. The resulting total score, in combination with prior treatment location and principal ICU diagnosis, is entered into a logistic regression equation. The equation (which is proprietary) provides a predicted mortality. A unique feature of APACHE III is that it uses daily updates of clinical information, which can be linked to computerized ICU patient records, to provide a dynamic predicted mortality score
requires the input of a large amount of detailed physiologic data, and requires proprietary computer technology

52. Treatment Options
The major goals of treating the cirrhotic patient include:
Slowing or reversing the progression of liver disease
Preventing superimposed insults to the liver
Preventing and treating the complications
Determining the appropriateness and optimal timing for liver transplantation

53. Liver Transplantation
Liver transplantation is the definitive treatment for patients with decompensated cirrhosis
Depends upon the severity of disease, quality of life and the absence of contraindications

54. Liver Transplantation
Minimal criteria for listing cirrhotic patients on the liver transplantation list include
A child-Pugh score 7
Less than 90 percent chance of surviving one year without a transplant
An episode of gastrointestinal hemorrhage related to portal hypertension
An episode of spontaneous bacterial peritonitis

55. Vaccinations Hepatitis A and B Pneumococcal vaccine
Influenza vaccination
Vaccination of cirrhotic patients against hepatitis A and B can help prevent a superimposed insult to a liver that may have little functional reserve

56. Surveillance Screening recommendations:
serum AFP determinations and ultrasonography every six months
The benefit of surveillance for hepatocellular carcinoma is controversial since a reduction in mortality from surveillance programs has not been consistently demonstrated. Despite the uncertainty, many hepatologists screen cirrhotic patients with serum AFP determinations and ultrasonography every six months

57. Avoidance of Superimposed Insults
Alcohol
Acetaminophen
Herbal medications
avoid any agent that has the potential to cause additional liver injury
abused substances such as alcohol, over-the-counter medications (such as high doses of acetaminophen), prescribed drugs with hepatotoxic side effects, and certain herbal remedies.
Although the exact amount of acetaminophen that is safe in cirrhosis is uncertain, we recommend that patients not use more than a total of 2 g per day (in divided doses).

58. References Up to Date Harrison’s New England Journal
Nail abnormalities: clues to systemic disease, American Family Physician, March 15, 2004 Robert Fawcett