The term “ascites” dates back as far as the fourth century BC, when Hippocrates described the condition. He used the Greek word askos, meaning a leather bag or sheepskin used to carry wine, water, or oil. Hippocrates realized that not only was ascites directly related to a diseased liver but it was also likely to be fatal. In one of his famous aphorisms, Hippocrates wrote, “When the liver is filled with water and bursts into [the omentum], in this case the belly is filled with water and the patient dies.” A century later, Erasistratos of Chios proposed a mechanistic explanation, writing that ascites was “a chronic and scirrhous inflammation of the liver or spleen, which prevents the assimilation of the food in the bowels and its distribution through the body, but changes it into water, which being refrigerated, is deposited between the intestine and the peritoneum.” Some aspects of this description remain essentially accurate today.
In modern language, ascites is the abnormal accumulation of fluid inside the abdominal, or peritoneal, cavity. It has numerous causes, but the symptoms are fairly uniform: a distended abdomen, weight gain, and sometimes swelling in the legs. When the ascites is large enough, it presses on the diaphragm and patients feel short of breath. The peritoneal cavity is normally a potential space that exists between the lining of the abdominal wall (called the peritoneum) and the organs that occupy the abdomen. These organs lie right up against the abdominal wall, and other than a tiny amount of fluid that can be normal, there is no “space.” When fluid begins to accumulate, which it can do for many different reasons, it is called ascites. One of the most important as well as most common causes is liver disease. The liver, a large solid organ located in the right upper quadrant of the abdomen, is a complex chemical factory. The raw materials are the by-products delivered to the liver from the last meal from the intestines. The finished products are the usable building blocks to be metabolized or stored elsewhere in the body.
Because of this critical function, the liver has two independent sources of blood flow. The first is the hepatic artery. This vessel brings oxygen-rich blood from the heart to the liver. The second source of blood is from the portal vein. Everywhere else in the body, the veins carry blood away from a tissue and back to the heart, but the portal vein is unique. It does drain blood away from a tissue—the intestines—but the blood does not flow straight back to the heart. The portal vein first delivers all the nutrients from the intestines to the liver. The liver processes these chemical substrates, storing some of the result in the form of glycogen and packaging the rest to be distributed to other parts of the body, such as fat and muscle. These chemical building blocks that the liver manufactures (triglycerides, free fatty acids, and amino acids) are then drained away from the liver and back to the heart by the hepatic vein. Thus, two vessels bring blood to the liver—the hepatic artery and the portal vein—and one vessel, the hepatic vein, drains blood from the liver back to the heart.
In certain forms of liver disease, the blood that flows into the liver is partially blocked from leaving. This can occur from liver scarring in cirrhosis (the “scirrhous inflammation” of Erasistratos) or liver fibrosis, or from a blockage of the hepatic vein. When the venous pressure in the liver builds up, the lymph from the surface of the liver begins to “sweat” into the abdominal cavity. Heart failure is another cause of this same kind of ascites. If the heart is not pumping effectively, the blood backs up in the hepatic vein and the same train of events is triggered. Another cause of blood backing up is when the hepatic vein clots or becomes otherwise obstructed. In each of these situations, the result of backed-up plumbing is called portal hypertension, or increased pressure in the portal vein. One manifestation of portal hypertension is ascites.
Another cause of ascites is infection in the peritoneal cavity. In past centuries, tuberculosis was an important cause of infectious ascites. Today, peritonitis caused by normal bacteria that live in the intestine and cross over into the abdomen is the most common infection. Sometimes this occurs spontaneously in the presence of liver disease, other times after the perforation from appendicitis or some other abdominal catastrophe.
Cancer, particularly mesothelioma related to asbestos exposure, and metastatic cells from ovarian cancer, are relatively common causes of ascites. Just about any cancer can spread to the peritoneum and lead to ascites.
To diagnose the specific cause of ascites, doctors perform a simple procedure that has been used since the time of Hippocrates. The procedure is called paracentesis. After cleaning the skin with an antibacterial solution and anesthetizing it (two upgrades since the fourth century BC), the physician inserts a sterile needle directly into the abdomen. Fluid is withdrawn into a syringe, after which it is analyzed in the laboratory to test the protein level and to look for microorganisms or cancer cells.
Joanne was hospitalized in May for a battery of tests to determine the cause of her ascites. There were the usual perfunctory blood and urine tests; some showed trivial abnormalities like a slightly low protein level and a slightly high enzyme (called the LDH) level, but nothing of any diagnostic consequence. She was subjected to a nuclear isotope liverspleen scan, an ultrasound exam, and even a liver biopsy. This test showed some mild fibrosis, but again, nothing diagnostic. She then had an upper GI series and finally a paracentesis to directly test the ascites fluid. The ultrasound showed a probable fibroid tumor in her uterus, but this was thought to be a benign growth that was unrelated to her symptoms. Despite the thoroughness of the testing during her ten-day hospitalization, there were no definitive results.
She did not like being cooped up in a hospital; she could neither eat nor exercise the way she was used to. Young remembers, “I was like a mad woman. I missed the exercise. All I wanted to do was get out of the hospital. I was practically running up and down the hallways. And my doctor wasn’t into nutrition. He was surprised at all the vitamins I was taking. In fact, I had to smuggle them into the hospital. I felt like I was doing drugs.”
After all the tests came back negative, she was discharged. Several days later, she went to her gynecologist, who was still concerned about the possibility of ovarian cancer, so he wanted to schedule a more invasive test—a laparoscopy. This procedure, now commonplace, was relatively new back in 1981. A surgeon inserts a rigid metal tube through a small incision in the abdomen, and through the tube it is possible to examine the contents of the abdomen and perform some surgical procedures.
Joanne recalls that visit vividly. “I wasn’t thrilled, obviously. My daughter was with me; she was pregnant at the time. We left the doctor’s office and went out to lunch to discuss all the ‘what if ’s.’ I decided that if I had cancer, I was going to fight it with everything I had.”
The laparoscopy was done on June 8, 1981. The procedure itself went smoothly. “He told me everything looked fine,” recalls Young. Three days later, however, she received a phone call from the doctor. The news wasn’t good. “He was my daughter’s obstetrician at the time and one of my running partners. His voice was all broken up. He said, ‘I don’t know how to tell you this, Joanne, but we found some cancer cells.’ He referred me to a gynecologic cancer specialist in Boston, Dr. Thomas Leavitt, who practiced at the Brigham and Woman’s Hospital.” After examining her, Leavitt ordered another round of tests. She underwent a barium enema, an abdominal CT scan, a D&C (a gynecologic procedure to test for uterine cancer), mammograms, and endoscopic examinations of the lower intestine and bladder.
All of the tests were negative; there was no evidence of a malignancy. However, the doctors in Boston decided to do another paracentesis, and yet again, Joanne’s ascites fluid revealed cancer cells.
It was now August. To try to get to the bottom of the problem in the most definitive manner, Dr. Leavitt scheduled open abdominal surgery to directly inspect the internal organs. This approach would allow him to biopsy and remove any suspicious tissue. The surgery went without a hitch. The findings: no cancer, and somewhat surprisingly, no cancer cells in the abdominal fluid.
Yet the flu
id, which had receded somewhat over a three-month period, was beginning to accumulate again. “And I was starting to feel lousy and weak,” Joanne recalls. “After a while, I couldn’t run or even bike; the pressure from the fluid made it hard to breathe. At one hospital visit, they drained four and a half quarts of fluid through a catheter. Six weeks after the abdominal surgery, I felt terrible.”
In September, Young was referred to yet another physician, Dr. Charles Trey, who was a gastroenterologist and a liver specialist at the nearby New England Deaconess Hospital. Joanne had so much fluid that it was beginning to accumulate around her lungs, and she was no longer the picture of health. Dr. Trey remembers her as a “bubbly and vivacious woman,” but her physical health had flagged severely and an excerpt from his clinical notes reads, “She was cachectic [emaciated] with a markedly distended abdomen. . . . There was obvious wasting of her temporal muscles and her eyes were sunken.”
“She was very health conscious,” recalls Trey, “but I was concerned because she used so many vitamins and enzymes and herbal teas. I first thought the problem might be vitamin A toxicity.” Excess vitamin A sometimes causes a liver problem, but blood tests eliminated that possibility. Looking for all sorts of unusual diagnoses, Trey tested for excess copper, iron, mercury, and zinc, and for diseases with names like paroxysmal nocturnal hemoglobinuria and porphyria. All were normal. To help improve her breathing, he removed more fluid from the abdomen, and this time he also removed fluid from around her right lung. He tested the fluid for tuberculosis and other infections—again, with negative results.
Trey did, however, solve one mystery: the reason for the cancer diagnosis. The cells that twice had been interpreted as malignant were the large cells that line the abdominal cavity, called mesothelial cells. When these mesothelial cells become inflamed, they can change their shape and appearance under the microscope and mimic cancer cells. On careful reexamination, they proved to be completely benign.
Although the possibility of cancer had been eliminated, there was still no diagnosis. Dr. Trey now thought that the leading possibility was a condition called the Budd-Chiari syndrome.
Budd-Chiari syndrome applies to a group of disorders, the common denominator of which is obstruction of outflow from the liver (blockage of the hepatic vein) that results in severe ascites. The first report of this condition, in 1845, is ascribed to Dr. George Budd, a distinguished physician who practiced in London. He wrote extensively on disorders of the liver, although his contribution to this entity was relatively minor. In 1899, the Austrian pathologist Hans Chiari published the first pathological description of the entity that now bears his name.
Most cases are caused by a blood clot in the major hepatic vein, but there are many other causes. In fact, in Chiari’s original report, he wrote about an inflammatory process that resulted in clotting of the small veins draining the liver, not the large hepatic vein itself. The increased pressure in the liver leads to portal hypertension, which in turn results in ascites.
Trying to establish a diagnosis of Budd-Chiari syndrome, Dr. Trey repeated a liver biopsy, this time getting a deeper sample of tissue. The findings were supportive of a diagnosis of Budd-Chiari, but not conclusive. Nowadays, a simple CT scan could make the diagnosis, but this was 1981, so Dr. Trey ordered a hepatic venogram, a specialized x-ray procedure in which a catheter is threaded into one of the larger veins in the body—the vena cava—and then dye is injected into the hepatic vein. The dye outlines the veins themselves, and the doctor can also measure pressures in the veins. Any large clot in the hepatic vein will be visible. The pressure measurements confirmed Trey’s suspicions, but there was no large clot. So while he had unraveled one more layer of the enigma— his patient had Budd-Chiari syndrome—he still lacked a specific diagnosis. What was causing the high portal pressures in Joanne Young’s liver?
Budd-Chiari syndrome is usually caused by disorders that are characterized by a tendency for blood to clot too easily, and Dr. Trey’s workup tested for all of these conditions, but those tests also proved negative. At this point, the list of potential causes of the problem was growing thin.
Young’s condition was also deteriorating, and the need for treatment was becoming increasingly urgent. Trey next consulted with Dr. William V. McDermott, a professor of surgery at the Harvard Medical School and chief of surgery at the Deaconess Hospital. Both physicians agreed that to prevent liver failure, Joanne needed surgery to halt the inexorable progression of the ascites. The kind of surgery they proposed, called a porto-caval shunt, is basically a sophisticated plumbing job that shunts the blood away from the high pressure portal system into the low pressure vena cava.
Shortly afterward, McDermott performed the surgery to reduce the pressure in her portal vein. The surgery was successful. Recalls McDermott, “That cleared up her ascites as you would it expect it would, but post-operatively, I was really baffled as to what could have caused this.” The patient was discharged, feeling markedly improved but still without a complete understanding of what was causing her problem. Not too long after the surgery, in December 1981, nine months after her symptoms first began, Young suffered from a brief complication called hepatic encephalopathy, a state of confusion that results when the body tries to process large amounts of protein that is bypassing the liver by way of the shunt that McDermott had created.
With treatment, the encephalopathy rapidly cleared up, but early in 1982, McDermott and Trey remained mystified by the cause of the inflammation of Joanne’s liver. One day, the two doctors and a Harvard medical student who was involved in Young’s care, Paul Ridker, were reviewing the case and discussing the various herbal preparations that Joanne had been taking. That is when they got the final clue needed to solve the mystery. Trey had observed from the very beginning that Young was an avid consumer of herbal and natural products. He and McDermott remembered an obscure study published almost thirty years earlier, about Jamaicans with an atypical pattern of liver disease— and a diet that included herbal tea.
In the 1950s, a doctor noticed an unusual liver problem in Jamaicans who drank “bush teas”—concoctions prepared using various wild plants. Physicians from the University College of Medicine in Jamaica reported a series of five cases of an odd form of liver disease with prominent ascites. The patients were children (the oldest was eighteen), and their liver biopsies showed findings strikingly similar to that described in Chiari’s original work. These children had all been drinking bush teas, which contained various plants. These investigators suggested that substances in the bush tea were causing the liver disease.
A far larger epidemic of approximately sixteen hundred cases occurred in Afghanistan in the early 1970s. The report from the Lancet, published in 1976, goes as follows:
During 1970 –1972, the north-western region of Afghanistan was hit by severe drought. The brunt of the calamity fell on the district of Gulran, affecting a population of about 35,000 in 98 villages. The district consists of undulating hills with scanty vegetation serving as pasturelands. Water is scarce and obtained from shallow wells and small springs. Communications are very poor, and during the winter the villages are snowbound and totally isolated. The inhabitants are illiterate and the principal occupation is farming. Their diet consists of wheat bread and occasional meat. During the years of drought, the flocks of sheep and goats were mostly destroyed, and there was a serious shortage of food.
Toward the middle of 1974, cases of huge abdominal distention and emaciation started to appear in the villages and soon assumed epidemic proportions. The poorest families were disproportionately involved. In many instances, several members in a family were affected within weeks of each other and all had died.
The illness began gradually, with loss of appetite, fatigue, and muscle wasting. Most of the patients had enlarged livers and massive ascites. Nearly 25 percent of the region’s population developed liver disease, and many died, since access to medical care in the area was poor. In villagers who were investigated at a hospital,
the liver specimens showed the same findings as in the Jamaican children who drank the bush tea, and in autopsy material from some of the fatal cases, the doctors found the same occlusive disease of the small veins that Chiari had described.
As for the cause of the epidemic, an important clue emerged from one of the villagers. This man, a shepherd, had observed the same effects on his flock of sheep, which he had fed some of his wheat crop that was overgrown by a weed. When he went to slaughter the sheep, he found that most of the animals had shrunken, scarred livers and large amounts of ascites. From the beginning, the researchers thought the disease was most likely caused by some sort of toxic exposure. They fairly quickly ruled out chemical fertilizers, preservatives, and pesticides. Because of the shepherd’s testimony and because of the appearance of the liver lesions, the possibility of contaminated plants immediately became a serious one.
A plant called Heliotropium was found to be growing in the wheat fields, and when the grain was harvested, the Heliotropium had been gathered along with it. The wheat was then ground into flour, the Heliotropium seeds were pulverized too, and the bread made from the wheat unintentionally included Heliotropium flour. Families that had cleaned out the intruding plants from the wheat did not develop liver disease. In the other families, there were often several members who were affected simultaneously.
The Deadly Dinner Party: and Other Medical Detective Stories Page 21