I met Isaiah Abraham Wagler the way I meet all my patients, cocooned in glass. A slide containing a small slice of his liver lay before me. I positioned it on the cool black stage of the microscope. Tinted blue and red to reveal the delicate cellular structures, the tissue looked like the tortuous flow of a red river. From what I could see, the overall structure of Mr. Wagler's liver seemed sound, but there were faint strands of gray, the first signs of long-term damage. The gray strands told me his liver was slightly scarred. Something was awry.
About a month before, Mr. Wagler had complained of a dull pain in his belly after meals. His family doctor had ordered an ultrasound, which revealed hard clumps of cholesterol, called stones, in his gallbladder. Stones can form when the liver isn't producing the right ratio of chemicals in the digestive fluid called bile. After a preliminary blood workup, Mr. Wagler's gallbladder was removed. During the operation the surgeon, Dr. Evans, noted a slight grayish brown discoloration of the liver, and he took a snippet and sent it to me, the pathologist.
I switched the microscope to medium power and began to scan the red field. The liver is laid out, like a vast honeycomb, in a series of hexagons called lobules. The nutrients and blood from the gut enter at the edges of the lobule and pass through hepatocytes, or liver cells, on their way to the central vein of each lobule. There the blood collects and enters the venous system, on the way to the heart. I could see that the overall lobular structure of the liver was still preserved. There was a little scarring at the edges but no sign of cirrhosis, the medical term for scarring so severe that the liver cannot function normally-or heal.
I began searching for other clues. There were none-no clumps of search-and-rescue immune cells, no tissue reaction, no signs of injured or dying cells. If Mr. Wagler's liver was scarred from alcoholism, I would expect the cells to look blurry, the intricate cellular scaffolding to be in ruins. Or if the virus that causes hepatitis had invaded the cell, the nucleus would look broken up, as if a bomb had gone off inside. But I saw nothing but a little scarring. These scars, though, were the gravestones of dead hepatocytes.
I switched the microscope to the highest power and closed in on the soft pink of a hepatocyte. The hepatocyte is one of the hardest-working cells in the body. It takes the raw material from the gut and breaks it down into amino acids, simple fats, and sugars and then reassembles it into complex proteins, lipoproteins, and carbohydrates. The hepatocyte makes the factors that clot our blood and the albumin that helps keep blood within blood vessels. It also stores our vitamins. Moreover, the hepatocyte detoxifies us. It deactivates alcohol, barbiturates, and other drugs. It adds a molecule to bilirubin, a component of bile, which then dissolves in water and is excreted. If the liver fails to do this, bilirubin accumulates in the body, causing the yellow skin of jaundice. The liver does all this without a single moving part.
Even at high power, I couldn't see anything but normal cells. Then I compared hepatocytes near the edge of the lobule with the ones near the central vein, and I began to see a slight-very slight-difference. The hepatocytes near the edge had a bit of brown pigment that the hepatocytes in the center of the lobule seemed to lack. Bile? Perhaps. It is a normal product of the liver. Lipofuscin? It certainly could be. Lipofuscin is a brown pigment that shows up in our cells when we age. I needed to do a little detective work.
I leaned back from the microscope and picked up the biopsy requisition form. Beside Mr. Wagler's name was his age-31-and his address, a rural route near Montgomery, Indiana, a small hamlet of fewer than 300 people. Most likely he was a farmer. He was too young for the pigment to be lipofuscin, which usually appears in the elderly. The pigment was probably bile. But if it was bile, he should be jaundiced.
I walked across the hall and printed out the results of his blood tests. There was not a lot, just a routine, normal blood count and simple blood test results. His glucose and albumin, both liver products, were normal, but his liver enzymes were a bit high. That indicated a continued low level of liver injury. His bilirubin level was normal, however. He was not jaundiced, so the pigment in the liver probably was not bile. But what was it? I returned to my desk and looked again at the requisition form. Just below his name was the abbreviation AMIS. He was Amish.
The Amish, who settled here in southwest Indiana in 1868, represent a growing part of our community. I see them almost every day, either in the hospital or at the Wal-Mart. The married men wear beards without mustaches, and the women wear long dresses and bonnets. They tend to travel into town as a family.
The Amish are prized among patients. They tend to be obedient, they rarely sue, and in this age of HMOs, PHOs, Medicare, and Visa cards, the Amish are the rarest of the rare-they often pay in cash.
I began to summarize my findings. Mr. Wagler was a young Amish man with gallstones that had brought him to the doctor. There appeared to be no relationship between the gallstones and his true disease, the chronic disorder of the liver. To help him, I needed to find an agent that could kill slowly and silently, cell by cell.
Almost all the killers of the liver leave telltale traces. A viral infection like hepatitis would produce inflammation, signs of immune cells attacking infected cells. And if the liver was under attack by misguided immune cells, as in some autoimmune disorders, inflammation would also appear. The common toxins, such as alcohol and acetaminophen, would produce, in part, a fatty liver. All the external killers I could recall leave signs. Then I began to wonder if the killer was not a foreign agent. What if the killer was always there? Just unknown. What if the killer was in his genes? Did Mr. Wagler have a genetic disorder? The Amish are a small religious community that doesn't mingle much with others, and they are known to have an increased incidence of certain genetic diseases. This can happen in any small, isolated community in which members intermarry.
I looked once more at the slide of Mr. Wagler's liver, scanning the cells near the edge of the lobule. They looked grainy and golden brown, and I thought for a moment about iron. There is a hereditary disorder, called hemochromatosis, that causes the liver to accumulate too much iron. It fit the profile of a silent killer. But hemochromatosis usually shows up in older people. I had never seen a case so early. To test for it, I needed to stain the liver for iron. The stain releases the iron from its bonds with proteins. When the reaction is complete, the freed iron absorbs so much light that the tissue looks blackish blue. If Mr. Wagler was accumulating too much iron, his tissue would look Prussian blue, the deep blue of a Van Gogh.
The next morning the stain was ready. I placed the slide of the liver under the lens of the microscope and focused on the cells near the edge of the lobule. A field of blue lay before me. Iron. Mr. Wagler's liver was filled with iron, much more than the brown pigment I could see with the standard stains.
Our bodies carefully regulate the amount of iron we absorb, and one of the genes involved in this process causes hemochromatosis. When a patient inherits mutations in this gene from both his mother and father, iron gradually builds up in his body-sometimes reaching 50 to 100 times the normal amount in the liver and pancreas. Over the years, iron accumulates in those organs as well as in the heart, spleen, and joints and irreversibly injures them. In its final form, hemochromatosis causes cirrhosis, heart failure, diabetes, arthritis, and a grayish pigmentation in the mucous membranes.
The disorder is a medical student's delight. So many organs are damaged, and all the pathophysiological manifestations can be explained by a single diagnostic entity. In medical school, everyone learns how to recognize hemochromatosis in its final form. But it is a diagnosis only a medical student could love, because if diagnosed in its late stage, hemochromatosis is uniformly fatal. However, if caught early, the condition is completely treatable. Mr. Wagler's liver was in the early stage of the disease. If he began therapy, the dream I had had since medical school could be fulfilled.
Nearly a quarter of a century has passed since my first day in Erlanger Auditorium at Washington University Medical School. That day our dean, John Herweg, a gray man in a gray suit, rose from a sea of young, pink faces and took the podium.
"Today is the first day in a long journey," he said. "A journey that will add 10,000 words to your vocabulary in the first year alone. A journey that will transform you. Thirty-five years ago I sat here for my first day in medical school. I had a dream, a dream many of you may share: the dream to cure someone. Well, in all of those years, I have done that once. For the most part, all that I have been able to do is make the misery more bearable and delay the inevitable. I hope that you, too, will find these acceptable goals."
Dr. Herweg was right. In my years of practice, I have always been too late. The disease had gone too far. But for Mr. Wagler, if the diagnosis was hemochromatosis, there was a chance. I had taken the case as far as I could. To be sure that Mr. Wagler was indeed suffering from hemochromatosis and not some other disorder with similar symptoms, I needed a more precise measure of the iron accumulation. It was time for further testing and a second opinion.
I sent Mr. Wagler's tissue, along with his medical history, to the Mayo Clinic. For good measure, I also enclosed the slide of his gallbladder. Three days later I received a phone call from Kenneth Batts, the clinic's senior gastrointestinal pathologist.
"I agree," said Batts. "The diagnosis is homozygous hemochromatosis with no evidence of cirrhosis."
"What about the gallbladder?"
"That was nothing but stones, unrelated. May I keep the slide of the liver? I'd like to show it to our residents so they will know what to look for."
I guess for Mr. Wagler, the stones were lucky stones: they'd brought him to the doctor. Over the next few months, Mr. Wagler was treated with one of the oldest therapies in medicine-bloodletting, or phlebotomy. Hemochromatosis responds well to phlebotomy. Indeed, it is why most women with hemochromatosis are protected from the disease until they are past menopause. The menses bleed away excess iron.
Every week, Isaiah Wagler came to the hospital to have a pint of blood removed. In less than a year his iron decreased to normal. For the rest of his life, a pint drawn every three or four months should prevent any damage from iron buildup. During his phlebotomy therapy, we tested his brother and found that he, too, had the disorder.
Our understanding of the genetics of hemochromatosis has advanced rapidly since we diagnosed these cases three years ago. A test can now detect the defective gene in 85 percent of hemochromatosis cases. Physicians are being encouraged to become more aware of the disorder, which affects an estimated 1.5 million Americans.
In pathology, there are no slaps on the back from happy patients; we are the invisible physicians, hidden behind a glass wall. Our patients rarely meet us. About a month after I signed out the case of Mr. Wagler, I received a phone call from the hospital cashier's office. I donned my white coat and walked down the long hallway toward the glass cubicle. As I neared, I saw four small children playing jacks outside. Inside, at the cashier, stood a woman in a bonnet and a large bearded man in blue and black. I slipped into the cubicle, and without introduction the man said, "The cashier says I owe you $110."
I nodded. He turned, took the money from his pocket, and methodically began to count out the bills. There was no sound, except for the whisper of the bills hitting the cashier's table. I glanced beyond the glass of the cubicle at Mr. Wagler's children, then reached over and put my hand on his. "No, this one's on me."
With his back still turned, Isaiah Wagler paused and then put the money in his pocket. Then he turned to face me. He looked every inch the weathered farmer-broad and sturdy, with bones like oak and skin like burlap. He shook my hand and thanked me.
